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Flavonoids in Cancer and Apoptosis

Mariam Abotaleb, Samson Samuel, Elizabeth Varghese and 4 more

Cancers · 2018 · Review · CC BY

doi:10.3390/cancers11010028

Abstract

Cancer is the second leading cause of death globally. Although, there are many different approaches to cancer treatment, they are often painful due to adverse side effects and are sometimes ineffective due to increasing resistance to classical anti-cancer drugs or radiation therapy. Targeting delayed/inhibited apoptosis is a major approach in cancer treatment and a highly active area of research. Plant derived natural compounds are of major interest due to their high bioavailability, safety, minimal side effects and, most importantly, cost effectiveness. Flavonoids have gained importance as anti-cancer agents and have shown great potential as cytotoxic anti-cancer agents promoting apoptosis in cancer cells. In this review, a summary of flavonoids and their effectiveness in cancer treatment targeting apoptosis has been discussed.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Cancer is a heterogeneous disease triggered by irreversible impairment of cellular homeostasis and function. Cancer progression is a result of uncontrolled cell growth and differentiation along with loss of apoptotic functions leading to a massive expansion in neoplastic cells population. Internal causes of cancer may be attributed to lack of apoptotic function, genetic mutations, oxidative stress, and hypoxia, while external causes of cancer may be linked to excessive exposure to ultraviolet rays, radiation, pollution, smoking, and stress. There are six hallmarks that contribute tumorigenesis and distinguish cancer cells from normal healthy ones (Figure 1).

2. Apoptosis

Apoptosis is a stringently organized process, regulated by a series of signal transduction cascades and cellular proteins. Cancer and many other diseases such as AIDS, diabetes, and Parkinson’s syndrome, occur as a result of imbalances and aberrant mechanisms in apoptotic pathways. Thus, a profound understanding of apoptotic mechanisms and related pathways not only serves in comprehending the disease but also in disease treatment.

2.1. Apoptotic Proteins

Classification of apoptotic proteins depends primarily on their role in apoptosis (Figure 2B). Pro-apoptotic proteins are further classified depending on the protein family into (1) caspases and (2) Bcl2 family:

(1) Caspases, aspartate-specific cysteine proteases possess a key role in apoptosis induction and are usually found as inactive heterodimers known as procaspases. There are 14 known proteins belonging to caspases classified according to their structure and function (Figure 2A).

(2) Bcl-2 family (Figure 2B) regulates cells behavior through programmed cell death. Localized to the outer membrane of the mitochondria, it mainly modulates the release of cytochrome c. Bcl-2 family of proteins is structurally distinguished by the presence of a BH3 domain. Bcl-2 family either induces apoptosis via multi domain Bax/Bak or inhibits anti-apoptotic proteins (IAPs) belonging to BH3 only family including Puma, Noxa, Bim, Bad, Smac/Diablo, Hrta/Omi, Arts. Puma and Noxa which are crucial in cytokines induced apoptosis are produced as a result of DNA damage and transcription of P53. Bad (which is induced by nutrition deprivation and growth signals), Smac/Diablo, Hrta/Omi, and Arts are all produced as a result of MOMP. Anti-apoptotic proteins (Figure 2B), members of the Bcl-2 family functioning as apoptosis inhibitors, are subclassified into multi BH domain containing Bcl-xL, Bcl-B, Bcl-W, Mcl-1, Bf1 Diva/Boo. Under unstressed cellular conditions these proteins are upregulated in order to bind, interact, and sequester the pro-apoptotic Bax and Bak, preserving the mitochondrial membrane integrity. BIR domain of anti-apoptotic proteins include N-IAP, c-IAP 1, c-IAP 2, and x-IAP. Testis specific survivin and ubiquitin conjugating enzymes livin and bruce/appollon all function mainly through the inhibition of caspases.

2.2. The Apoptotic Pathway

Two major pathways contributing to apoptosis are shown in Figure 3. Firstly, the extrinsic/death receptor induced pathway and secondly, the intrinsic pathway in which mitochondrial stress is involved. In extrinsic pathway the activation of signal transduction cascade occurs via binding of death signals to trimeric death ligands such as Fas and TNF. Once an extra cellular death signal is received, initiator procaspases-8 and -10 (bound to the inner membrane FADD/TRADD regions of death receptors) are activated which results in the formation of a DISC complex and thus the signal transduction cascade proceeds. Subsequently, activated caspase-3 functions in the activation of the mitochondrial amplification loop through the Bid protein containing BH3 only domain, thus serving as a link between extrinsic and intrinsic pathways. t-Bid, an active form situated on the mitochondrial membrane, is responsible for the intrinsic cascade via the activation of pro-apoptotic multi-domain Bcl-2 proteins Bax and Bak. Activated Bax and Bak mediate increasing MOMP through the formation of pores and change of the mitochondrial membrane potential (ΔΨm), resulting in the release of cytochrome c. Cytochrome c, Apaf 1 protein, and procaspase-9 form an apoptosome, enhancing the apoptotic cascade through activation of executioner caspases.

Mitochondrial pores also facilitate the release of Smac/Diablo and Hrt/Omi which are BIR family inhibitors acting via inhibition of caspase-9. Intrinsic pathway could also be activated internally through oxidative stress, hypoxia, increased intracellular concentration of intracellular calcium ions, infection, or withdrawal of growth factors that obstruct the pro-apoptotic Bad protein that also stimulates Bax and Bak. The activation of Bax and Bak is mediated through the inhibition of anti-apoptotic proteins Bcl-xL and Bcl-2. The function of Bak is restricted via VDAC. The activation of IAPs occurs as a result of the overexpression of tumor suppressor gene TP53 resulting in the activation of pro-apoptotic BH3 only domain proteins Bid (inhibiting Bcl-xL), Noxa (inhibiting Bcl-2) and Puma (inhibiting Mcl-1), all contributing to Bax-Bak pore formation and the release of cytochrome c. p53 functions in the process of ROS induction and increase of cellular stress as it was proven that ROS could enhance caspase function. ROS also stimulates H2O2 production, shifts the intracellular pH, and favors the activation of Bak. In addition, O2− modulates the function of VDAC, hence increases mitochondrial membrane permeability. p53 is also associated with lysosomal permeabilization, releasing cathepsin that activates Bid and Bak on the mitochondrial membrane. Moreover, p53 is related to the activation of procaspase-2 through its release from p53-induced protein with a death domain PIDDOSOME. Subsequently, caspase-2 enhances the activation of t-Bid, boosting the mitochondrial amplification loop. The MOMP pathway activates AIF and Endo G that increase DNA fragmentation. Moreover, the release of Smac/Diablo inhibits the function of BIR domain family, preventing the inhibition of caspase 9. Cytochrome c factors in the release of Ca2+ ions through the activation of Inositol 1,4,5 phosphate on the surface of the ER to mitochondria resulting in accumulation of Ca2+ in mitochondrial space, hence increasing mitochondrial stress and pore formation. Increased intracellular Ca2+ ion concentration also triggers the activation of calpain, an intracellular endonuclease that targets the decomposition of nuclear and cellular membranes. In addition to function of caspase-3 in mitochondrial loop amplification, caspase-3 is also considered to be an executioner caspase, inhibiting and cleaving PARP associated with DNA repair process. PARP activates CAD which contributes to DNA fragmentation, as well as activation of Lamin A, resulting in chromatin condensation and nuclear membrane degradation. Inter alia, the formation of apoptotic bodies is realized after activation of fodrin. Already mentioned reactions/pathways lead to characteristic physiological and morphological alterations such as cell shrinkage and blebbing (pyknosis), formation of apoptotic bodies, and membrane changes influenced by the phosphatidyl serine “Annexin V” allowing phagocytic cells to attack. Accordingly, chromatin condensation (karyorrhexis), DNA fragmentation, breakdown of nuclear membrane, and increase of mitochondrial membrane permeability as well as high consumption of ATP are included in such alterations.

Cancer cells show resistance to apoptosis mediated by over expression of oncogenic genes (such as c-Myc, which enhances cellular proliferation and suppresses p53), and anti-apoptotic proteins (Bcl-2, survivin, livin, etc.). In contrast, the resistance of cancer cells to apoptosis can be also modulated via down regulation of pro-apoptotic proteins (caspases, Bad, Bax etc.) and the loss of tumor suppression function of p53. Overcoming resistance in apoptotic pathways is an interesting approach in cancer treatment. This is mainly achieved through targeting p53 (drug, gene and immunotherapy), caspases (drug and gene therapy) and BIR family, and stimulating the action of IAP. Recently, plant-based treatment of cancer has been a highly active area of research across the globe. In this review, effects of flavonoids in cancer treatment and their influence on apoptotic pathways will be discussed.

3.1. Classification of Phytochemicals

Phytochemicals are bioactive non-nutrient compounds widely distributed in plants with an ability to reduce the risk of various diseases. There are more than 50,000 different known phytochemicals in plant kingdom. The basic classification of phytochemicals is provided in Figure 4.

Significantly, phenolics possess one or more aromatic benzene ring and could be mono or poly hydroxylated. Moreover, phenolics are considered to be the most abundant antioxidants in human diet. Phenolics are classified as non-flavonoids including phenolic acids, stilbenes, tannins, coumarins, and flavonoids.

3.2. Flavonoids

Flavonoids are secondary plant metabolites responsible for color and aroma of flowers, and they possess antibacterial, antiviral, antioxidant, anti-allergic, and anti-inflammatory abilities. In the process of carcinogenesis, flavonoids interfere with multiple signal transduction pathways and thus limit proliferation, angiogenesis, and metastasis or increase apoptosis (Figure 5A,B).

Polyphenolic terpenoids consist of 15 carbon atoms arranged as a chromane ring (A and C) linked to a B ring in either C2 (Flavonoids) or C3 (isoflavonoids). As illustrated in Figure 5A,B, they could be further classified according to the C ring saturation and oxidation into 5 major classes. Each class differs in the degree of hydroxylation and substitution. Flavonoids exist either as glycosides with attached sugars or as aglycones with no attached sugars.

3.2.1.1. Flavanone

Flavanones, also known as di-hydroflavones, are characterized by a saturated, oxidized C ring. Flavanones are distributed in citrus fruits and are known for their antioxidant activity and free radical scavenging ability. Hesperetin and naringenin are two main flavanone compounds (Figure 6).

(A) Hesperetin

Hesperetin or 5,7,3′-trihydroxy-4′-methoxyflavanone is an aglycon present abundantly in citrus fruits, cherries, and tomatoes. Hesperetin and its glycoside, hesperidin, are known for their neuroprotective, vascular, anti-inflammatory, anti-allergic, antioxidant, and anticarcinogenic effects. Hesperetin exerts anticancer abilities either by elevating ROS, attenuating mitochondrial potential, inducing DNA fragmentation, or by over expressing Fas and FADD ligands. Pro-apoptotic effects of hesperetin were evaluated by both in vitro and in vivo studies. Hesperetin induced expression of cytochrome c, APAF-1, caspases-3 and -9 and reduced Bax to Bcl-2 ratio in gastric cancer cells. Hesperetin was also found to induce cellular cell death in Eca109 cells by increasing ROS and decreasing GSH concentrations, confirming intrinsic mitochondrial cell death. Similar pro-apoptotic effects were related to HT-29, MCF-7, and MDA-MB-231 cells. Moreover, in the HT-20 cell line, hesperetin decreased the concentration of enzymatic antioxidants such as SOD, CAT, and GPx. Conversely, in H522 cells, hesperetin induced apoptosis extrinsically via overexpression in Fas and FADD ligands, increase in caspase-9, and downregulation of p53 levels. Furthermore, hesperetin was found to induce intrinsic and/or extrinsic apoptosis and cell cycle arrest at G2/M phase in the SiHa cell lines. In addition to the inhibition of NF-κB pathway, hesperetin reduced Bcl-2 transcription and translation in PC-3 cell lines.

(B) Naringenin

5,7,4′-trihydroxyflavanone, also known as naringenin, is an aglycone found mostly in oranges and grapefruits. It has a broadly remarkable pharmacological profile and a wide range of biological effects, including anticancer, antioxidant, antimutagenic, antiproliferative, and anti-inflammatory abilities. Anticancer properties of naringenin are induced either by elevating ROS, reducing mitochondrial potential, inducing DNA damage, or extrinsically by overexpression of Fas and FADD ligands. In a study conducted on SGC-7901 cells, naringenin induced apoptosis via increase in p53 expression, PARP cleaving, Bax and caspase-3 cleaving, and also decrease in the expression of Bcl-2 and survivin. Moreover, in A431 and HepG2 cells, naringenin arrested cell cycle at G0/G1 and/or G2/M phase, decreased ΔΨm, and increased the caspase-3 or Bax/Bcl-2 ratio. Considering HepG2 cells, in vivo studies revealed that naringenin increased cytochrome c and AIF/Endo G mobilization from the mitochondrial membrane, and reduced GSH concentration, SOC and, catalase activity. Similarly, naringenin treatment of MCF-7 cell lines resulted in activation of caspase-3. Furthermore, a naringenin synthesized derivate (N101-2) induced cell cycle arrest at sub-G1 phase in SiHa cells. Accordingly, intrinsic apoptosis was modulated due to elevated levels of p53, caspases-3, -8, and -9; increased PARP; and upregulation of Bax. On the contrary, extrinsic apoptotic pathway was confirmed by overexpression of Fas/FasL. In HeLa and PC-3 cells, naringenin increased intracellular ROS level and induced loss of ΔΨm.

3.2.1.2. Flavanols

Also known as catechins, flavan-3-ols are profoundly distributed in bananas, apples, peaches, pears, and blueberries. Similar to flavanone, flavanol is characterized by a saturated C ring. However, it is usually unoxidized and possesses a hydroxyl group at C3. Catechins can exert cell cycle arrest via modulation of multiple signaling pathways such as nuclear factor-κB, MAPK, epidermal growth factor, vascular endothelial growth factor, and matrix metalloproteinase. Flavanols are subdivided into epicatechin and epigallocatechin gallate (Figure 7).

(A) Epicatechin

Epicatechin is widely distributed in dark chocolate, grapes, and green tea. Epicatechin is known to be a potent antioxidant contributing to apoptosis and preventing angiogenesis by modulation of signaling enzymes activity Antiproliferative properties of epicatechin were observed in both HeLa and MKN-45 cells in which H2O2-mediated oxidative stress led to the rapid destruction of cancer cells. The findings of other studies suggested that epicatechin is also able to target proliferative signaling Akt and NF-κB. Interestingly, epicatechin in combination with panaxadiol or cisplatin showed synergistic pro-apoptotic effects in HCT-116 or renal tubular carcinoma respectively.

(B) Epigallocatechin Gallate (EGCG)

EGCG has been reported to induce apoptosis in many cancer cell lines. In prostate carcinoma cells EGCG considerably induced TRAIL-mediated apoptosis and, similarly, in small cell lung carcinoma EGCG increased caspase-3 activity. Moreover, EGCG increased Bax/Bcl-2, p53, p21, caspases-3, and -9, PTEN and down-regulated PI3K, AKT, and Bcl-2 in T47D and HFF cells. EGCG was also found to stimulate p21 and p27 expression in MDA-MB-468, MDA-MB-231 and HS578t cells, moreover, it inhibits Ki-67 in (PRB)-E2F/DP pathway. Antiproliferative properties of EGCG were conducted on human esophageal squamous carcinoma cell lines in vitro and tumor xenografts in vivo. EGCG was found to exert cell cycle arrest at G1 phase in Eca-109 and Te-1 cells while the apoptosis was accompanied by elevated levels of ROS and caspase-3 cleavage. Considering in vivo experiment, proliferation was inhibited via decrease in VEGF. Moreover, in HT-29 cells EGCG induced apoptosis due to Akt, ERK1/2 or p38 MAPK inhibition. Furthermore, pro-apoptotic effects of EGCG were demonstrated in 293T cells via modulation of Bax/Bcl-2, caspases, and cytochrome c release. A dose-dependent cytotoxic effect of EGCG was observed in A549 cells due to the reduction of Bcl-xL. Gupta, S. et al., reported that EGCG decreased cell proliferation in induced apoptosis via inhibition of the NF-κB/p65 nuclear translocation. In MCF-7 breast cancer cells EGCG inhibited the phosphorylation of ErbB2 and ErbB3 and suppressed the MAPK pathway, while in mammary tumor NF639 and SMF cells EGCG reportedly decreased cell proliferation, phosphorylation of ErbB2/neu and inhibited the NF-κB and MAPK pathways. In SW837 colon cancer cells EGCG reportedly reduced the cellular levels of EGFR, ErbB2 and ErbB3.

3.2.2.1. Flavonol

Flavonol is characterized by the unsaturated C ring at C2-C3, which is found oxidized at C4 and hydroxylated at C3. Flavonol is widespread in kale, lettuce, onions, grapes, and berries. Flavonols are classified into six groups (Figure 8).

(A) Quercetin

3,5,7,3′,4′-Pentahydroxyflavone or quercetin is the most abundant flavonoid, widely distributed in barks, flowers, and seeds of tomatoes, apples, berries, grapes, onions, tea leaves, Brassica vegetables, capers, shallots, and nuts. Quercetin is a phytoestrogen structurally resembling endogenous estrogen 17β-estradiol. Several studies support the anticancer potential of quercetin. In MCF-7 cells, quercetin showed the tendency to induce both apoptosis via increase of Bax, capsase-3 and decrease in Bcl-2 and necroptosis through overexpression of RIPK1 and RIPK3. Another study demonstrated the ability of quercetin to induce intrinsic mitochondrial apoptotic pathway. On the contrary, quercetin enhanced extrinsic apoptosis in the BT-474 cell lines. Interestingly, it had no effect on Bcl-2 or Bax and therefore did not initiate any intrinsic apoptotic pathway.

Mitochondrial-induced pro-apoptotic effects of quercetin were demonstrated in HL-60 cell lines via modulation of Cox-2, caspase-3, Bax, Bad, Bcl-2, cytochrome c, and PARP. In BC1, BC3 and BCBL lymphoma cells, quercetin induced apoptosis via downregulation of PI3K/AKT/mTOR and STAT3 pathways. Quercetin in combination with EGCG reduced cell viability via inhibition of MDR1 in PC-3 and LNCaP cells. Moreover, effective reduction of LNCaP over PC-3 suggests that quercetin also mediates p53 apoptotic pathway. In a similar manner when co-administered with metformin, quercetin inhibited the proliferative PI3K/AKT pathway. While quercetin decreased ErbB2 tyrosine kinase activity and the phosphorylation of PI3K and AKT om SKBR3 breast cancer cells, it reduced the phosphorylation of ERK1/2 and AKT phosphorylation and inhibited the NF-κB pathway in HepG2 liver cancer cells.

(B) Kaempferol

Kaempferol or 3,4,5,7-tetrahydroxyflavone is a nontoxic dietary flavonoid distributed in tea, kale, beans, onions, tomatoes, strawberries, broccoli, cabbage, apples, and grapes. Kaempferol possess antioxidant, anti-inflammatory, antimicrobial, neuroprotective, and anticancer abilities. Kaempferol structurally resembles estrogen, thus it could have dual estrogenic/antiestrogenic effects depending on its concentration, and could be a candidate in treatment of hormonal based cancers such as ovarian, breast, and cervical; hepatocellular carcinoma; acute promyelocytic leukemia; and glioma. In breast cancer MDA-MB-453 cells kaempferol induced DNA fragmentation and upregulation of p53 expression and phosphorylation leading to disrupting cell proliferative signaling, hence apoptosis. Kaempferol was associated with the induction of intrinsic apoptosis in the A2780/CP70, A2780wt and OVCAR-3 cell lines via mitochondrial pathway in which increase of caspase-3, caspase-7, p53, Bax, Bad, and decrease in Bcl-xL was included. Kaempferol also decreased the proliferative signaling of Akt pathway and prevented angiogenesis via downregulation of VEGF. Similar effects were observed in the case of HL-60 and NB-4 cells. In another study, kaempferol synergistically increased the effect of cisplatin through overexpression of c-Myc in OVCAR-3. In HepG2 cells, kaempferol was found to induce apoptosis via ER stress and CHOP pathway. Moreover, kaempferol enhanced apoptosis via mitochondrial membrane depolarization and down regulation of the expression of anti-apoptotic proteins x-IAP and survivin in A172 cells. Additionally, in HeLa cell lines, kaempferol was associated with modulation of mitochondrial function and apoptosis via elevating the Bax/Bcl-2 ratio.

(C) Fisetin

3,7,3′,4′-Tetrahydroxyflavone, also known as fisetin, can be found in strawberries, apples, persimmons, grapes, onion, and cucumber. Fisetin is reported to possess neurotrophic, anticarcinogenic, and anti-inflammatory properties. Fisetin showed the tendency to induce apoptosis in the LNCaP cell lines via the induction of PARP cleaving, release of cytochrome c, cleavage of caspases-3, -8, -9, increase of Bad, Bax and Smac/Diablo and downregulation of Bcl-2, Bcl-xL and x-IAP. In DU145 and PC3 cells fisetin decreased the activity of NF-κB. In addition, the co-treatment of cancer cells with TRAIL and fisetin caused significant activation of caspases-3 and-8 and disruption of the mitochondrial membrane. Similarly, fisetin was associated with reduction of cell viability and induction of apoptosis in SNU-1 cell lines. Fisetin exhibited similar effects in HeLa cells both in vitro and in vivo via modulation of ΔΨm, caspases-3, -8, and Bax/Bcl-2 ratio leading to cleavage of PARP. Moreover, pro-apoptotic abilities were associated with fisetin in combination with sorafenib in xenografts. Interestingly, fisetin induced ER stress mediated apoptosis in NSCLS. Significantly, combinatorial treatment of fisetin and melatonin in MeWo and Sk-mel-28 cells resulted in cleavage of PARP protein, mitochondrial release of cytochrome-c, and inhibition of COX-2 and NF-κB proteins. Furthermore, in U266 cells fisetin increased sub-G1 population, caspase-3 activation, over expression of Bax, Bim, and Bad; downregulation of Bcl-2 and Mcl-1; and continuous generation of ROS.

(D) Myricetin

3,5,7,3′,4′,5′-Hexahydroxyflavoneis or myricetin is a common dietary flavonoid found black tea, green tea, or wine. Myricetin is associated with antibacterial, antiviral, antioxidant, and anti-carcinogenic activities. Protective role of myricetin against cancer was demonstrated in HCT-15 cells by DNA condensation, suppression in Bcl-xL and Bcl-2 expression, and increase in the release of mitochondrial AIF. However, no effect on the cleavage of caspases-3 and -9 was observed. In UVB induced HaCaT cells, myricetin exerted pro-apoptotic effects via inhibition of Akt pathway. Decrease in the Bad phosphorylation, ΔΨm and release of cytochrome c, Smac, and AIF were also observed. Furthermore, in SKOV3 cells myricetin induced nuclear chromatin condensation and fragmentation and DNA double strand breaks in dose-dependent manner. In cisplatin resistant OVCAR-3 and A2780/CP70 cell lines myricetin overcame cancer chemoresistance and exhibited higher cytotoxicity than cisplatin. The underlying mechanism involved both intrinsic and extrinsic apoptotic pathways confirmed by regulated expression of Bcl-2 and DR5 respectively. Finally, the mechanism of myricetin induced apoptosis in TNBC was comprehended by the induction of ROS that resulted in DNA double strand breaks, and activation of mitochondrial apoptotic pathway.

(E) Galangin

3,5,7-Trihydroxyflavone also known as galangin is highly concentrated in honey and propolis, and in the Chinese herb, lesser galangal. Findings of several studies suggested anticancer properties of galangin. The effect of galangin was tested on male and female human colon cancer cell lines HCT-15 and HT-29 respectively. Results illustrated caspase and mitochondrial dependent apoptotic pathways including DNA condensation, activation of caspases-3 and -9, release of AIF, and loss of mitochondria membrane potential. In SNU-484 cells galangin induced apoptosis and inhibited cellular proliferation in both dose- and time-dependent manner. Changes in cell morphology, PARP cleavage, DNA fragmentation, activation of caspases-3 and -9, and MAP kinase pathway were all observed in treated cells. In HepG2, Hep3B, and PLC/PRF/5by cell lines, galangin showed pro-apoptotic tendencies through translocation of Bax to the mitochondria, decrease in Bcl-2 expression, activation of caspase-8 and Bid, release of cytochrome c, and PARP cleavage. Moreover, pro-apoptotic effects of galangin in B16F10 cells were associated with disruption of ΔΨm cleavage of procaspases-3 and -9 and PARP and p38 MAPK pathway. Furthermore, galangin also reversed TRIAL resistance in Caki, ACHN, and A498 cells by downregulation of Bcl-2, c-FLIP, Mcl-1, and survivin, and inhibition of NF-κB pathway. Galangin in combination with berberine synergistically led to cell cycle arrest in Eca9706, TE-1 and EC109 cells at G2/M phase.

(F) Casticin (vitexicarpin)

3′,5-Dihydroxy-3,4′,6,7-tetramethoxyflavone, or casticin, is well known for its strong pharmacological profile and use as an anti-inflammatory, neuroprotective, analgesic, immunomodulatory, and most importantly estrogenic and anti-carcinogenic agent. In vitro investigation on human NSLC cell lines H460, A549 and H157 showed 50% reduction of cell viability associated with membrane depolarization, mitochondrial release of cytochrome c, activation of caspases-3 and -9, increase of DNA fragmentation, downregulation of x-IAP and Bcl-xL proteins, and upregulation of Bax and Bid. In BGC-823, SGC-7901, and MGC-803 cell lines and in human colon cancer HT-29, HCT-116, SW480, casticin induced apoptosis intrinsically by down regulation of c-FLIP, Bcl-2, x-IAP, and survivin. Extrinsic pathway was potentiated by TRAIL-induced cytotoxicity as it intensely upregulated DR5 receptor expression with no effects on DR4 or decoy receptors. Treatment of PANC-1 cells and PC-3 cell lines with casticin led to the induction of apoptosis and cell cycle arrest via altering Bax/Bcl-2 ratio and activation of caspase -3. Similar effects were observed in U251, U87, and U373 cells. In xenografts of NOZ and SGC996 cells, casticin inhibited proliferation, induced apoptosis, and caused cell cycle arrest at G0/G1 via mitochondrial apoptotic pathway in which modulation of Bax, Bcl-2, cyclin D, caspase-3, -9, and PARP were observed.

3.2.2.2. Flavones

Flavones are distributed mainly in leaves, flowers, and fruits. Celery, parsley, mint, chamomile, red peppers, and ginkgo biloba are considered to be rich sources of flavones. Similar to flavonols, their structure is comprised of an unsaturated C ring at C2-C3 position and a ketonic group at C4, but unlike flavonols they lack hydroxylation at C3. Flavones include apigenin, chrysin, luteolin, baicalein, tangertin, acacetin, flavopiridol/alvocidib, wogonin, and eupatorin (Figure 9).

(A) Apigenin

Apigenin or 5,7,4′-trihydroxyflavone is a phytoestrogen aglycone abundantly found in vine spinach, oranges, garlic, parsley, celery, carrot, propolis, artichokes, oregano, and chamomile. Apigenin anticancer efficacy in PC-3, 22Rv1, and DU145 cells resulted from the inhibition of HDAC enzymatic activity on transcriptional and translational levels leading to hyperacetylation of H3 on the p21/waf1 promoter. Correspondingly, Bax overexpression, knockdown of x-IAP, c-IAP1, c-IAP2 and survivin, Bcl-2 and Bcl-xL proteins, as well as the release of cytochrome c were also observed. Moreover, in SCC25 and A431 cells, apigenin alone or in combination with 5-fluorouracil (5-Fu) or cisplatin led to cell cycle arrest at G2/M phase via augmenting levels of ROS, reducing glutathione, and inducing TNF-R and TRAIL-R. Apigenin also suppressed ACHN, 786-0, and Caki-1 RCC cell proliferation in vivo through cell arrest at G2/M phase, DNA damage, and p53 upregulation. In T24 cell line, apigenin inactivated PI3K/Akt pathway, cyclins phosphorylation of p53, p21 and p27, activated the caspase cascade, released cytochrome c, downregulated Bcl-xL, Bcl-2m Mcl-1 and upregulated Bax, Bad and Bak. In SW480 xenograft model, apigenin induced alteration in expression of cyclin D1, BAG-1, Bcl-2, and FADD which led to apoptosis. Moreover, in BCPAP cells, apigenin inhibited viability in a dose-dependent manner due to enhanced ROS and subsequent induction of DNA damage. In HCT-116 cells, apigenin induced intrinsic, extrinsic, and ER stress-initiated apoptosis together with increase of ROS and decrease in mitochondrial membrane potential and Ca2+ generation. Apigenin upregulated protein expression of CHOP, DR5, BID, Bax, cytochrome c release, and caspase cascade -3, -8 and -9. Apigenin reportedly reduced ligand induced phosphorylation of EGFR and ErbB2 thereby impairing their downstream signaling and thus induces apoptosis in head and neck squamous carcinoma cells. Additionally, apigenin inhibited the proliferation and survival of malignant mesothelioma cells in vitro, increased the intracellular production of reactive oxygen species and induced DNA damage. The apigenin induced cell death was related to the increase in the Bax/Bcl-2 ratio, p53 expression, the activation of caspases 9 and 8 and cleavage of PARP-1. In an in vivo C57BL/6 mouse model of malignant mesothelioma transplanted with #40a cells, intraperitoneal administration of apigenin reduced the risk of tumor growth and increased median survival rates in the apigenin treated mice. Shukla, S. et al., reported that apigenin treatment decreased cell proliferation, increased proportion of cells in G0/G1 phase and decreased the levels of Rb and p38 kinase.

(B) Chrysin

5,7-dihydroxyflavone, or chrysin, is a flavonoid abundantly found in Thai propolis and honey. Chrysin is an apigenin analogue with high therapeutic potential favorable to intestinal membrane transport. However, its low bioavailability due to rapid metabolism and excretion renders its use less beneficial when compared to other flavonoid compounds. Chrysin demonstrated high potency as an aromatase inhibitor in addition to its well-known role as an anti-inflammatory, antioxidant, and cancer chemo-preventive agent. Chrysin was reported to be the most potent flavonoid functioning in the reduction of cell viability and induction of apoptosis in HeLa cell lines via increased DNA fragmentation and induction of p38 and NF-κB/p65. In Bcl-2 overexpressing U937 cell lines, chrysin showed pro-apoptotic effects through activation of caspase-3 and increased degradation of PLC-1, in addition to downregulation of x-IAP and inactivation of Akt. Moreover, TRAIL-induced apoptosis associated with chrysin was observed in A549 and HeLa cell lines. TRAIL-induced cell death was selectively induced via inhibition of STAT3 and knockdown of Mcl-1. TRAIL-induced cell death after chrysin treatment was also observed in HCT-116 and CNE1 cells. Recently a fully elucidated mechanism was exploited in DU145 and PC-3 cells including loss of MMP, increase in ROS, ER stress, and suppression of PI3K. In SP6.5 and M17 melanoma cultured cells, chrysin activated mitochondrial dependent apoptotic pathway via loss of membrane potential, cytochrome c release, and activation of caspases-3 and -9 but not -8. Chrysin alone or in combination with cisplatin in HepG2 and QGY7701 cancer cells induced intrinsic and extrinsic apoptotic pathways due to increased levels of p53, Bax, caspases-3, -8, and -9 and DR5 along with decreased Bcl-2 levels.

(C) Luteolin

Luteolin or 5,7,3′,4′-tetrahydroxyflavone, is a well-known chemo-preventive, anti-inflammatory, and a cytotoxic chemotherapeutic agent. In HepG2 cells, luteolin increased concentration of cytochrome c, translocated mitochondrial Bax and Bak and activated JNK pathway. In a tumor xenograft model, luteolin activated AMPK and NF-κB signaling and the release of ROS. In NSLC A549 luteolin activated JNK, increased Bax, and promoted cleavage of caspases-3 and-9. Moreover, luteolin induced cytotoxicity, increased expression of p53 and p21, decreased MDM4 protein expression, and activated caspases-3 and -9 in vivo. In NCI–H4 60 cells treated with luteolin apoptosis was modulated intrinsically, extrinsically, and via ER stress. Similarly, ER stress and elevation of ROS in vitro and in vivo were observed in U251MG and U87MG cells. The combination of luteolin with chemotherapeutic drugs 5-fluorouracil or gemcitabine synergistically induced anti-proliferative activity as reflected by decreased protein expression of nuclear GSK-3b and NF-κB, and increased cytochrome c. In PANC-1, CoLo-357, and BxPC-3 luteolin increased Bax/Bcl-2 ratio associated with an increase in caspase-3, cleavage of PARP, and inhibition of NF-κB. The Co-administration of luteolin and paclitaxel in MDA-MB-231 cells in mice xenografts resulted in reduction of tumor size via an increase in activated caspases-3 and -8 and increased expression of Fas. Luteolin also inhibited metastatic breast cancer cell lines by reducing expression of VEGF. Luteolin was reported to induce intrinsic and extrinsic apoptotic pathway in HeLa cells via enhancement of caspase-3 and -8 activation cascade; reduction of ΔΨm associated with a release of cytochrome c; inhibition of Bcl-2 and Bcl-xL expression; and upregulation of death receptors Fas/FasL, DR5/TRAIL, and FADD.

(D) Baicalein

5,6,7-Dihydroxyflavone, or baicalein, is an aglycone found abundantly in the root of S. baicalensis. Baicalein is known for its extensive pharmacological anti-inflammatory, anti-cardiovascular, and anti neuro-degenerative effects. Its pro-apoptotic effect on cancer cells is both mitochondria and receptor mediated, accomplished mainly by modulation of Bcl-2 family. In SCC-4 cells, baicalein elevated Bax and lowered Bcl-2, modulated the release of cytochrome c, and activated the caspase cascade. Moreover, baicalein increased DR5 and TRAIL at protein and transcription levels and also elevated the level of ROS and induced ER stress. Similar anti-proliferative effects of baicalein were observed in PCa cells. Furthermore, in BxPC-3 and PANC-1cell lines baicalein suppressed proliferation and metastasis through reduction of Akt and ERK activities. In CRC HT-29 baicalein induced cell cycle arrest in the G1 phase, DNA fragmentation, chromatin condensation; decreased Bcl-2 and increased Bax expression; reduced MMP-9; and controlled Akt. In mice xenografts, baicalein modulated Akt and p53 dependent pathway and reduced expression of MMP 2/9. Baicalein treatment in SGC-7901 cells in vitro and in vivo through disruption of ΔΨm, modulation of Bax/Bcl-2 in a dose-dependent manner. Furthermore, in MDA-MB-231 cells pro-apoptotic effects of baicalein were associated with disruption of mitochondrial potential, release of cytochrome c, activation of caspases-3 and -9, increased Bax/Bcl-2, and elevated p53 expression and elevated signaling of ERK/p38 MAPK pathway. In addition, baicalein significantly inhibited invasion and metastasis by reducing the expression of MMP-2/9 and downregulating MAPK. Baicalein downregulated Bcl-2 and upregulated caspase-3, -8, Bax, and Fas/FasL in HeLa cells. Additionally, baicalein induced ER stress; upregulated Bax; downregulated Bcl-2, and induced cleavage of caspases-3, -9, and PARP in HCC cells in vitro and in vivo. Similarly, baicalein inhibited tumor cell proliferation and induced G2/M arrest in HCC J5 cells.

(E) Tangertin

5,6,7,8 4′-Pentamethoxyflavone, also known as tangertin, can be found in citrus peel oil of the tangerine and other citrus fruits. Tangertin was found to reduce DMBA-induced oxidative stress in breast cancer Sprague–Dawley rats by decreasing antioxidant enzymes SOD, CAT, GPx, GST, GSH, ascorbic acid and α-tocopherol. In addition, tangertin was found to cause cell cycle arrest at G1/S phase via p53/p21 up-regulation, and inhibited metastasis by suppressing MMP-2 and -9 and vascular endothelial growth factor. In AGS, in a dose-dependent manner, tangertin induced apoptosis via p53 dependent mitochondrial dysfunction and Fas/FasL extrinsic pathway. Tangertin also suppressed p53 inhibitor PFT-α via upregulation of p53, caspases-3, -8, and -9 activity, and Bax, t-Bid, p53, Fas, and FasL. Moreover, in U-87MG and LN-18 tangertin induced G2/M arrest and apoptosis by modulating PTEN and cyclin-D and cdc-2 mRNA and protein expressions. Additionally, tangertin in combination with TRIAL in H1299 and H1975 cells downregulated anti-apoptotic Bcl-2, Bcl-xL, survivin, x-IAP, c-IAP1, and c-IAP2 and elevated expression of pro-apoptotic Bax and caspases-3, -8, and -9. In addition to a significant increase in expression of DR 4 and 5, induction of ER stress was mediated via upregulation of CHOP and elevation of ROS.

(F) Acacetin

Acacetin is 5,7-dihydroxy-4′-methoxyflavone extracted from safflower flowers. Acacetin is associated with anti-peroxidative, anti-inflammatory, anti-plasmodial, and anticancer effects. In T cell leukemia Jurkat cells, acacetin induced apoptosis through alterations in nuclear and cell morphology; induction of caspases-3, -8, and -9 activity; release of Apaf-1 and cytochrome c; and an increase in Bax/Bcl-2 ratio in a time-dependent manner. The study conducted on the pro-apoptotic effects of acacetin in chronic lymphocytic leukemia (CLL) B-lymphocytes xenografts and healthy B-lymphocytes proved direct targeting of mitochondrial pathway via increased release of cytochrome c, caspase -3 activation, increased concentration of reactive oxygen species (ROS); and MMP collapse. Acacetin showed antimetastatic potential in DU-145 cells via inhibition of phosphorylation of p38 MAPK involved in the knockdown of expression of MMP 2 and 9, and u-PA at protein and mRNA levels. In addition, acacetin was found to influence chromatin condensation and ability to significantly deplete nuclear NF-κB, which is associated with downregulation of Bcl-2 and x-IAP and proliferative protein COX-2. Moreover, in MCF-7 and HSC-3 cell lines acacetin influenced growth inhibition, DNA fragmentation, and PARP cleavage; enhanced caspases-7, -8 and -9 activity; and decreased Bcl-2. Acacetin also decreased mitochondrial membrane potential, modulated release of AIF and cytochrome c, and enhanced ROS generation, which subsequently resulted in apoptosis.

(G) Flavopiridol/Alvocidib

Flavopiridol is a cyclin-dependent kinase inhibitor mainly targeting CDK 9 in phase II clinical trials. Flavopiridol has shown efficacy in the treatment of chronic lymphocytic leukemia (CLL) SU-DHL-4 and TMD8 cells. Generally, flavopiridol initiates cell cycle arrest and apoptosis in a p53-independent mechanism that involves the down regulation of anti-apoptotic Mcl-1 and x-IAP and induction of ER stress. In HCC the inhibitory effect of flavopiridol was associated with Mcl-1 inhibition that enhanced caspase-3 activation and PARP cleavage. Interestingly, doxorubicin applied in combination with flavopiridol in HCC mouse models significantly reduced proliferative signaling. Moreover, the anti-proliferative and pro-apoptotic effects of the flavopiridol in combination with oxaliplatin in melanoma cells and its subcutaneously injected allograft were associated with enhanced caspase -3, -7 and -9 activities in a dose dependent manner via the mitochondrial apoptotic pathway. In metastatic osteosarcoma U2OS, SaOS-2, SJSA-1, and 143B, at nanomolar concentrations flavopiridol treatment led to significant reduction of cadherin 3 and 4, thus reducing metastatic potential in lungs.

(H) Wogonin

Wogonin, or 5,7-dihydroxy-8-methoxyflavone, extracted from Scutellaria baicalensi is associated with antioxidant, anti-inflammatory, anticonvulsant, neuro-protective, anti-bacterial, and anti-viral effects. Wogonin in LNcaP cells elevated levels of p21, p27, p53 and PUMA, which are involved in apoptotic Bax signaling. Interestingly, wogonin in SK-N-BE2 and IMR-32 cell lines influenced mitochondrial dysfunction and ER due to the release of cytochrome c; altered expression of Bcl-2, Bax, and Bid; activation of caspases-3, -4, -8, -9, and -12; increased PARP cleavage; and ER stress-related proteins GRP-78 and GRP-94. In NSLC A549 and HeLa cell lines synergetic effects of wogonin and cisplatin were observed via potentiation of caspase-3 activity, and subsequent cleavage of PARP and H2O2 accumulation. The viability of HT-29 cells was suppressed in a dose-dependent manner after wogonin treatment via induction of cell cycle arrest at the G1 phase; increased DNA fragmentation, chromatin condensation, and Bax/Bcl-2 ratio, inactivation of PI3K/Akt pathway; and upregulation and activation in a p53. In A2780 cells wogonin inhibited proliferation and metastasis via reduction of VEGF, Bcl-2 and Akt expression, and augmentation of Bax expression and p53 caspase-3 cleavage Cytotoxic effects of wogonin were observed in HCC cell lines and xenografts via inactivation of AKT signaling, leading to the elevated levels of H2O2 and ER release of Ca2+. HPCC cells treatment of wogonin led to apoptosis due to enhanced ROS generation.

(I) Eupatorin

5,3′-Dihydroxy-6,7,4′-trimethoxyflavone, also known as eupatorin, is isolated from Orthosiphonstamineus, leaves of Lantana montevidensis, and in the aerial plants of Tanacetum vulgare. Eupatorin showed inhibitory effects on MDA-MB-468 cell lines at sub micromolar concentrations and in a dose dependent manner. Eupatorin led to cell cycle arrest at G2/M phase. The mechanism was elucidated by the selective activation of metabolic pathway of CYP1 to a cytotoxic active ingredient. Similarly, induction of cell cycle arrest at G2/M phase was also reported in HeLa cells. In addition to activation of BAX in a p53 independent pathway, Eupatorin upregulated p53, p21 caspases-3 and -7, and PARP cleavage. In HT-29 and SW948 cell lines, eupatorin decreased cell viability and induced apoptosis via a decrease in mitochondrial membrane potential, accompanied by an increase in Bax/Bcl-2 expression and an increase in ROS levels. Treatment of eupatorin in combination with doxorubicin in colon cancer simultaneously increased the Bax/Bcl-2 ratio, caspase-3 expression, and PARP cleavage and induced apoptotic cell death. In human leukemic cells it induced apoptosis via mitochondrial release of cytochrome c, activation of multiple caspases, and PARP cleaving. Finally, the induction of apoptosis and cell cycle arrest in HepG2 was effectively induced via modulation of p53, MAPKs, and the mitochondrial pathways.

3.2.2.3. Anthocyanidins

Anthocyanidins are characterized as a water-soluble, unsaturated, unoxidized class of flavonoids, occurring as plant pigments responsible for plant coloration depending on pH which contributes to their attractiveness.

The antioxidant activity of anthocyanins is based on their phenolic structure and multiple hydroxylation in position 3 of ring C and in the 3′, 4′ and 5′ positions in ring B of the molecule (Figure 10). Anthocyanidins (Figure 10) are associated with reduction of DNA damaging oxidative adducts, diminishing lipid peroxidation, inhibiting mutagenesis, and modulating signaling cascades, thus reducing cellular proliferation. Aglycons are usually more potent antioxidants owing to fewer number of sugar groups exhibiting wide pharmacological effects on cardiovascular disease and obesity, and antitumor, anti-inflammation, and anti-mutagenesis activities.

(A) Cyanidin

Cyanidin is usually found conjugated to a sugar, e.g., cyanidin-3-O-β-glucopyranoside (C3G). It has shown great effects in inducing cell cycle arrest, inhibiting proliferation (by impeding VEGF), metastasis (by the inhibition of MMP 2 and 9), and enhancing apoptosis caspase-independent AIF pathway (by activating cytochrome c and Bax protein expression) in various cancer cell lines. Antiproliferative effect of C3G in DU145 and LnCap cell lines was mediated through activation of caspase-3 and induction of p21 protein expression, along with an increase in DNA fragmentation and levels of tumor suppressor P75NGFR. In U87 cells, C3G showed pro-apoptotic effects via elevation of RNA expression of Bax and p53, whereas the expression of Bcl-2 was decreased.

Similarly, in MCF-7 cells, C3G mediated apoptosis via influencing morphological changes, surface blebbing, and nuclear condensation. Cyanidin induced apoptosis in RCC by enhancing caspase-3, inhibited metastasis via inhibition of E-cadherin, and inhibited tumor growth of nude mice xenografts. Cell cycle arrest at G2/M phase and DNA fragmentation were observed in U937 after cyanidin treatment. Finally, cyanidin-3,5-diglucoside, cyanidin-3-glucoside, cyanidin-3-rutinoside, and peonidin-3-glucoside blocked SMMC-7721 cells in vitro and H22 cells in vivo via inducing cell cycle arrest at G2/M, DNA damage, increase in the activities of antioxidase, and a decrease in the level of lipid peroxidation.

(B) Pelargonidin

Pelargonidin is an anthocyanidin that is abundant in berries. The acylated pelargonidin derivatives displayed a cytotoxic effect in Bel-7402 cells in a concentration-dependent manner associated with its antioxidant and pro-oxidant properties, along with influence on DNA damage. Pelargonidin-glucoside in HT-29 induced apoptosis via activation of caspase-3. Correspondingly, pelargonidin exposure to HT-29 cells caused the release of cytochrome c from mitochondria; upregulated the activities of caspase-3 and -9, Bax, and Bid; downregulated the expression of Bcl-2 and Bcl-xL in addition to cleavage of PARP; and induced the expression of p53 and p21waf1 I. Moreover, in U2OS cell line, pelargonidin triggered ROS-induced reduction in MMP and led to G2/M cell cycle arrest. In addition, pelargonidin also reduced the expression of proliferative cascades p-PI3K and p-AKT in a concentration-dependent manner.

(C) Delphinidin

Delphinidin is a major anthocyanidin found profusely in various colored fruits and vegetables, such as red cabbage, berries, sweet potatoes, and grapes. Delphinidin possesses anti-angiogenic, anti-inflammatory, anti-mutagenic, antioxidant, and anti-tumorigenic abilities. In SKOV3 cells, delphinidin reduced proliferation in a dose dependent manner through inactivation of PI3K/AKT and ERK1/2 mitogen-activated protein kinase signaling cascades. Similarly, in NSCLC delphinidin inhibited the activation of PI3K, phosphorylation of AKT and MAPKs; cleavage of PARP; activation of caspases-3 and -9; downregulation of Bcl-2, Bcl-xL, and Mcl-1; and upregulation of Bax and Bak. In mice xenografts significant inhibition of tumor growth along with an obvious decrease in cell proliferation markers Ki67, PCNA, and angiogenesis CD31, VEGF were also observed after the treatment. Furthermore, in B CLL, delphinidin-3-O-glucoside and delphinidin-3-O-rutinoside demonstrated pro-apoptotic effects through a redox-sensitive caspase -3 activation mechanism as well as dysregulation of the Bad/Bcl-2 pathway, by rapidly dephosphorylating Akt and Bad and downregulating Bcl-2. Additionally, delphinidin induces apoptosis and cell cycle arrest in highly metastatic human prostate cancer PC3 cells and androgen refractory human prostate cancer 22Rnu1 cells through the inhibition of several components of NF-κB pathway. Intra-peritoneal administration of delphinidin (2 mg), thrice a week, significantly reduced tumor growth in athymic nude mice implanted with PC3 cells (an in vivo model of prostate cancer). Investigations revealed that treatment with delphinidin significantly decreased the expression of NF-κB/p65, anti-apoptotic Bcl2, Ki67 and PCNA in these tumors.

3.2.3. Isoflavonoids (B Ring Attached to C3)

Distribution of isoflavonoids in plants is limited to soybeans and legumes, but they were also found in some microbes. Isoflavonoids are further subdivided into genistein and daidzein (Figure 11). High consumption of isoflavonoids was correlated with decreased risk of estrogen related cancers due to its estrogenic activity and ability to compete with 17β-estradiol in vitro and in animal models. It was also confirmed that isoflavones exert DNA photoprotective effects and upregulates the expression of glutathione peroxidase enzyme.

(A) Genistein

Genistein or 5,7,4′-trihydroxyisoflavone, is a phytosterol found profusely in soybeans. Genistein affected proliferation, differentiation, and apoptosis in MCF-7 and 3T3-L1 cells via regulating estrogen receptor-α (ERα) expression and altering Bax/Bcl-2 ratio. Cytotoxic action of genistein against MDA-MB cells involved prooxidant signaling due to the mobilization of endogenous copper Notch-1 pathway which resulted in inhibition of NF-κB activity, and downregulation of Bcl-2 and Bcl-xL. Moreover, in A2780, C200 cells genistein downregulated Bcl-2, Bcl-xL, c-IAP1, survivin, and NF-κB. In LNCaP cells genistein induced apoptosis via augmented TRAIL-induced disruption of mitochondrial membrane potential. The combination of Daidzein and genistein showed a synergistic effect on inhibition of cell proliferation and inducement of apoptosis in LNCaP and C4-2B. Similarly, combination of genistein and selenium in PC3 and LNCaP (hormone-dependent) significantly inhibited growth and metastasis in dose- and time dependent manner by decreasing the expression of in MMP-2, which has been associated with active invasion and metastasis. In HT-29 cell lines, the effect of genistein was explained by activating and dephosphorylating tumor suppressor FOXO3, which is usually attenuated by EGF. The potency of genistein against HT-29 colon cancer showed that apoptosis was induced by increased caspase-3 activity at the transcriptional, protein, and enzymatic levels and reduced matrix metalloproteinase-2 (MMP2) activity while it acted by inducing the mitochondrial pathway of apoptosis in HCT-116 and LoVo cells by inhibiting phosphorylation of Akt.

(B) Daidzein

7,4′-Dihydroxyisoflavone, also known as daidzein, is a dietary phytoestrogen isolated from soybeans. It is structurally similar to genistein; however, it lacks the hydroxyl group at position 5. Daidzein showed antiproliferative effects in different cancer cell lines. In MCF-7 cells and xenografts in a concentration- and time-dependent manner, daidzein stimulated production of ROS; release of cytochrome c from the mitochondrial membrane; activation of caspases-7 and -9; and alteration in Bax/Bcl-2 ratio. Daidzein was also involved in induction of apoptosis in HCCSK-HEP-1, associated with up-regulation of Bak and down-regulation of Bcl-2 and B-xL proteins; release of mitochondrial cytochrome c; APAF-1; and activation of caspases-3 and -9.

4. Final Remarks, Future Perspectives and Conclusions

Plant extracts have been proven to be strong candidates in the treatment of various types of cancer via modulating apoptotic pathway. The major mechanism involves the activation of apoptotic proteins intrinsically and extrinsically, elevation of ROS, and induction of DNA damage. The IC50 values of the various flavonoid compounds for various cancers discussed in the current manuscript is provided in Table 1.

4.1. Bioavailability

Bioavailability is the quantity of a compound that is absorbed and metabolized in the human body after it is ingested, and is commonly measured in terms of maximum plasma concentration (Cmax). Epidemiological data revealed an association between a diet rich in flavonoids and the prevention of human diseases. The efficacy of flavonoid compounds as cures and protective agents against a variety of human disease was tested extensively in in vitro experimental models and there remains a disparity between biological properties of flavonoids observed in vitro and their bioactivity in vivo. Similarly, while many of the naturally occurring flavonoids have the potential to be effective anti-cancer agents in vitro such beneficial effects cannot be achieved in humans primarily owing to the low bioavailability of many of these plant-derived secondary metabolites in the body. Hence the bioavailability of anti-cancer flavonoids must be investigated in detail. To explain the bioactivity of a flavonoid compound (the compound must enter the circulation and reach the tissues, in its native or metabolized form, in a sufficient quantity to exert biological activity) it is critical to understand the process of its absorption, bioavailability and its metabolism. In the body glycosylated flavonoids such as flavonols, isoflavones, flavones and anthocyanins are generally hydrolyzed into their respective aglycones by intestinal or colon microflora prior to absorption. The lipophilic aglycones enter the intestinal epithelial cells via passive diffusion while the epithelial transporters support the uptake of glycosides into the intestinal epithelial cells. The rate of absorption of glycosylated flavonoids are much lesser when compared to than aglycone flavonoids in the intestine. After absorption, flavonoids are subject to metabolic modifications primarily in the small intestine, liver and kidney. The post-absorptive metabolic changes such as methylation, sulfation, or glucuronidation of the flavonoids before entering circulation and target tissues could also vastly alter their biological properties. Additionally, the ingested flavonoid compounds, that remain unabsorbed in the proximal intestine, reach the colon where they are exposed to the colonic microbes which degrade these flavonoid molecules during which the heterocyclic oxygen containing ring is split and the subsequent degradation products (usually hydroxylated phenyl carboxylic acids) can then be absorbed. Gallic acid and isoflavones, flavanones, catechin and quercetin glucosides are known to have the highest bioavailability while anthocyanins and pro-anthocyanidins have the lowest.

In precision medicine major progress in understanding the bioavailability of several flavonoids has been made, but practical solutions to overcome the poor oral bioavailabilities of many of the flavonoid compounds are still lacking. Increasing bioavailability can be achieved by overstepping the barriers of solubility, cellular permeability, metabolic alteration and excretion of these compounds from the human body and facilitating target tissue uptake. Several research groups are attempting to enhance the bioavailability of protective flavonoid compounds by improving intestinal absorption, altering the site of absorption and improving metabolic stability. Although some of the flavonoid compounds are now commercially available in the form of pills, one must exercise caution because the use of large amounts of concentrated flavonoids may pose public health concerns owing to the limited information available on the adverse side effects and drug interactions of these compounds in an in vivo experimental setting and in clinical trials. Although debatable, studies reported that genistein, a soy isoflavone, stimulates the growth and proliferation of MCF-7 breast cancer cells by enhancing the insulin-like growth factor pathway even in the absence of hormones estrogen or progesterone.

There are several different biomolecules (carbohydrates and proteins) in the biological system that have the potential to affect the bioavailability flavonoids. Factors such as age, sex and genotype, in varying degrees can modulate the expression of bioactivity of these biomolecules which in turn influence the absorption, metabolism, circulating concentrations, tissue exposure and elimination of the ingested flavonoid compounds. Therefore, it remains an even bigger challenge to factor-in considerations on age, sex, ongoing disease condition/s, current medications, habitual diet (and physiochemical properties of the food) and nature of the gut microbiome to understand the bioavailability and efficacy of flavonoid compounds as anti-cancer drugs in clinical trials. In order to achieve the effective therapeutic doses used in preclinical studies importance must be given to improved and targeted drug delivery techniques so as to achieve maximum efficiency with minimal adverse side effects. Advances in nanotechnology-based drug delivery systems opens up better opportunities for increasing solubility, improving bioavailability and enhancing the targeting capabilities of flavonoids. Current research should focus on designing suitable molecular carriers for the flavonoid drugs to target tissues. Studies using nanoparticle (liposomes, poly-ethylene glycol liposomes, nickel-based, lecithin-based and nanoribbon) carriers for quercetin were reported to be successful in terms of drug delivery into solid tumors in in in vitro and in vivo models of cancers of the central nervous system, lungs, colon, liver and breasts.

4.2. Combination Therapy

Plant extracts have been proven to be strong candidates in the treatment of various types of cancer via modulating apoptotic pathway. The major mechanism involves the activation of apoptotic proteins intrinsically and extrinsically, elevation of ROS, and induction of DNA damage. Additionally, flavonoid-polyphenol/flavonoid and flavonoid-classical anticancer drug combinations reportedly have shown improved efficacy in the treatment of cancer.

A combination of pterostilbene and quercetin effectively reduced cell growth and proliferation, decreased Bcl-2 expression and increased cell death while decreasing the metastatic potential of B16M-F10 melanoma cells in vitro and decreased tumor growth, and improved survival rates in an in vivo mice model bearing B16M-F10 melanoma cells. Genistein and resveratrol in combination reportedly decreased tumor growth and IGF-1 expression in SV40 rats bearing prostate cancer xenografts. Genistein and thearubigin in combination showed synergistic effects and significantly reduced cell proliferation and caused G2/M phase cell cycle arrest in PC-3 prostate cancer cells. A combination therapeutic approach using quercetin and EGCG decreased cell proliferation, induced cell death and caused G2/M phase cell cycle arrest in PC-3 and LNCaP prostate cancer cells. In this combination of quercetin and EGCG, quercetin improved the bioavailability of the green tea polyphenol and decreased its post-absorptive methylation both in vitro and in vivo. In SCID mice bearing LAPC-4 prostate cancer cell xenografts the combination treatment using quercetin and EGCG was associated with a significant inhibition of tumor cell proliferation, decrease in androgen receptor expression, suppression of the PI3K/Akt signaling pathway and stimulation of apoptosis via increase in the Bax/Bcl-2 ratio. In another study luteolin and EGCG in combination reportedly at low doses (at which single agents induces minimal apoptosis) had synergistic effects and increased apoptosis in in both head and neck and lung cancer cell lines. The same study reported that the combination of luteolin and EGCG decreased tumor growth, inhibited Ki67 expression, increased cell death and reduced tumor growth in in vivo athymic mice models bearing xenografts of head and neck squamous cancer and lung cancer cells. The synergistic effects of the combination of luteolin and EGCG was attributed to increased phosphorylation of p53 and p53 dependent effects on cleavage of PARP and caspase-3. In MDA-MB-231 triple negative breast cancer cells, a combination of curcumin and EGCG decreased cell proliferation, growth, and viability and caused G2/M cell cycle arrest while decreasing tumor volume in athymic nude mice implanted with MDA-MB-231 cells which correlated to the decreased in the levels of VEGF receptor-1 (VEGFR1). Ellagic acid, a naturally occurring antioxidant occurring in walnuts, cranberries and strawberries potentiated the effects of quercetin on p21waf1/cip1, p53, and MAP-kinases in vitro. Combinations of ellagic acid and quercetin and quercetin and resveratrol decreased cell proliferation, increased cell death via the increase in caspase-3 activity and caused cell cycle arrest in MOLT-4 leukemia cells.

Suganuma et al., reported that EGCG in combination with tamoxifen or sulindac decreased the release of TNFα and decreased cell proliferation in PC-9 lung cancer cells and that EGCG stimulated the effects of celecoxib and decreased cell proliferation, increased the levels of GADD153 and phosphorylation of p38 in PC-9 and A549 lung cancer cells. In another study, a combination of EGCG and celecoxib reportedly decreased cell proliferation, growth and viability of LNCaP, PC-3 and CWR22Rv1 prostate cancer cells and decreased tumor growth, increased the Bax/BCl-2 ratio, PARP cleavage and the expression of caspases-3 and -9 while decreasing the NF-κB activity and serum levels of PSA and IGF-1. Combinations of EGCG with other anti-cancer drugs such as paclitaxel/docetaxel, doxorubicin, cisplatin, gemcitabine and tasocitinib effectively reduced cell proliferation, increased cell death, reduced tumor growth and improved survival rates in in vitro and in vivo models of cancers of the prostate, breasts, ovaries, liver and pancreas. Quercetin in combination with doxorubicin markedly reduced cell proliferation, DNA and protein synthesis and cell invasiveness in MCF-7 and MDA-MB-231 breast cancer cells. In HeP2 laryngeal cancer cells, a combination of quercetin and cisplatin decreased cancer cell proliferation and induced cell death/apoptosis which was mechanistically attributed to the decrease in the phosphorylation of Akt, in the levels of Bcl-xL and Ki67 and the activity of HSP70 while increasing the phosphorylation of JNK, c-fos expression, the Bax/Bcl-2 ratio, ROS production, activity of caspases-8 and -9 and release of cytochrome c. Combinations of genistein with other anti-cancer drugs such as cisplatin and gemcitabine, effectively reduced cell proliferation, increased cell death and reduced tumor growth in different in vitro and in vivo models of pancreatic cancers. Isoflavone treatment in PC-3 prostate cancer cells increased the susceptibility of these cells to radiotherapy both in vitro and in vivo, reduced tumor growth and metastasis to para-aortic lymph nodes while increasing the expression of Bax and PARP cleavage and decreasing the levels of Bcl-xL and survivin.

Ongoing and completed clinical trials have reported the safety and efficacy of polyphenols as anticancer agents. Clinical trials are also currently testing the flavonoid-flavonoid/polyphenol and flavonoid-anticancer drug combinations due to the promising pre-clinical data available on the use of such combinations. A phase I study showed the efficacy, safety and tolerability of muscadine grape skin extract (which contains ellagic acid, quercetin, and resveratrol) in men with biochemically recurrent prostate cancer. In breast cancer patients receiving radiotherapy administration of encapsulated EGCG (400 mg, thrice a day, orally) reduced the levels of VEGF and HGF in the serum and suppressed the activation of MMP-2 and MMP-9 and inhibited factors associated with the progression and metastasis of breast cancer. Additionally, the exposure of MDA-MB-231 cells to the serum of breast cancer patients who received a combination of EGCG and radiotherapy evidently suppressed MDA-MB-231 cell viability, caused G0/G1 cell cycle arrest and induced cell death by apoptosis.

Details of completed and ongoing clinical trials using quercetin, genistein, EGCG and various other flavonoids in the treatment of different cancers can be found at https://clinicaltrials.gov.

The use of drug combinations over single drug applications should prove beneficial in (1) decreasing the dosage/concentration of the drug being used, (2) improving bioavailability, (3) overcoming the resistance that can acquired against a drug, (4) sensitizing the chemotherapy/radiotherapy resistant cancers to treatment, (5) reducing cancer cell metastasis and invasion, (6) reducing chances of relapse and (7) improving overall efficacy of cancer treatment. Additional studies are warranted in order to examine the bioavailability, efficacy, safety, tolerance and drug delivery options for flavonoids to be used in the treatment of cancers.

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  15. 15.

    Chwieralski C.E., Welte T., Bühling F. Cathepsin-regulated apoptosis. Apoptosis. 2006;11:143-149.

    Not in our library10.1007/s10495-006-3486-y

  16. 16.

    Manzl C., Krumschnabel G., Bock F., Sohm B., Labi V., Baumgartner F., Logette E., Tschopp J., Villunger A. Caspase-2 activation in the absence of piddosome formation. J. Cell Biol. 2009;185:291-303.

    Not in our library10.1083/jcb.200811105

  17. 17.

    Boehning D., Patterson R.L., Sedaghat L., Glebova N.O., Kurosaki T., Snyder S.H., Insp R. Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis. Nat. Cell Biol. 2003;5:1051.

    Not in our library10.1038/ncb1063

  18. 18.
    Role of calpain in apoptosis. · 2011
    No notice
  19. 19.

    Stewart T.A., Yapa K.T.D.S., Monteith G.R. Altered calcium signaling in cancer cells. Biochim. Biophys. Acta. 2015;1848:2502-2511.

    Not in our library10.1016/j.bbamem.2014.08.016

  20. 20.
    Flavonoids: an overview · 2016
    No notice
  21. 21.

    Varghese E., Samuel S.M., Abotaleb M., Cheema S., Mamtani R., Busselberg D. The “yin and yang” of natural compounds in anticancer therapy of triple-negative breast cancers. Cancers. 2018;10:346.

    Not in our library10.3390/cancers10100346

  22. 22.

    Liu R.H. Nutrition, and cancer potential synergy of phytochemicals in cancer prevention: Mechanism of action 1. Int. Res. Conf. Food Nutr. Cancer Potential. 2004;134:3479-3485.

    Not in our library10.1093/jn/134.12.3479s

  23. 23.
    Anti-cancer potential of flavonoids: recent trends and future perspectives · 2013
    No notice
  24. 24.

    Tapas A.R., Sakarkar D.M., Kakde R.B. Flavonoids as nutraceuticals: A review. Trop. J. Pharm. Res. 2008;7:1089-1099.

    Not in our library10.4314/tjpr.v7i3.14693

  25. 25.

    Ravishankar D., Rajora A.K., Greco F., Osborn H.M.I. Flavonoids as prospective compounds for anti-cancer therapy. Int. J. Biochem. Cell Biol. 2013;45:2821-2831.

    Not in our library10.1016/j.biocel.2013.10.004

  26. 26.

    Kelly G.S. Quercetin. Altern. Med. Rev. 2011;16:172-194.

    Not in our library

  27. 27.

    Iqbal J., Abbasi B.A., Mahmood T., Kanwal S., Ali B., Shah S.A. Plant-derived anticancer agents: A green anticancer approach. Asian Pac. J. Trop. Biomed. 2017;7:1129-1150.

    Not in our library10.1016/j.apjtb.2017.10.016

  28. 28.

    Parhiz H., Roohbakhsh A., Soltani F., Rezaee R., Iranshahi M. Antioxidant and anti-inflammatory properties of the citrus flavonoids hesperidin and hesperetin: An updated review of their molecular mechanisms and experimental models. Phytother. Res. 2015;29:323-331.

    Not in our library10.1002/ptr.5256

  29. 29.

    Zhang J., Wu D., Vikash, Song J., Wang J., Yi J., Dong W. Hesperetin induces the apoptosis of gastric cancer cells via activating mitochondrial pathway by increasing reactive oxygen species. Dig. Dis. Sci. 2015;60:2985-2995.

    Not in our library10.1007/s10620-015-3696-7

  30. 30.

    Wu D., Zhang J., Wang J., Li J., Liao F., Dong W. Hesperetin induces apoptosis of esophageal cancer cells via mitochondrial pathway mediated by the increased intracellular reactive oxygen species. Tumor Biol. 2016;37:3451-3459.

    Not in our library10.1007/s13277-015-4176-6

  31. 31.

    Palit S., Kar S., Sharma G., Das P.K. Hesperetin induces apoptosis in breast carcinoma by triggering accumulation of ros and activation of ask1/jnk pathway. J. Cell. Physiol. 2015;230:1729-1739.

    Not in our library10.1002/jcp.24818

  32. 32.

    Sivagami G., Vinothkumar R., Preethy C.P., Riyasdeen A., Akbarsha M.A., Menon V.P., Nalini N. Role of hesperetin (a natural flavonoid) and its analogue on apoptosis in ht-29 human colon adenocarcinoma cell line—A comparative study. Food Chem. Toxicol. 2012;50:660-671.

    Not in our library10.1016/j.fct.2011.11.038

  33. 33.

    Elango R., Athinarayanan J., Subbarayan V.P., Lei D.K.Y., Alshatwi A.A. Hesperetin induces an apoptosis-triggered extrinsic pathway and a p53- independent pathway in human lung cancer h522 cells. J. Asian Nat. Prod. Res. 2017;6020:1-11.

    Not in our library10.1080/10286020.2017.1327949

  34. 34.

    Alshatwi A.A., Ramesh E., Periasamy V.S., Subash-Babu P. The apoptotic effect of hesperetin on human cervical cancer cells is mediated through cell cycle arrest, death receptor, and mitochondrial pathways. Fund. Clin. Pharmacol. 2013;27:581-592.

    Not in our library10.1111/j.1472-8206.2012.01061.x

  35. 35.

    Sambantham S., Radha M., Paramasivam A., Anandan B., Malathi R., Chandra S.R., Jayaraman G. Molecular mechanism underlying hesperetin-induced apoptosis by in silico analysis and in prostate cancer pc-3 cells. Asian Pac. J. Cancer Prev. 2013;14:4347-4352.

    Not in our library10.7314/apjcp.2013.14.7.4347

  36. 36.

    Patel K., Singh G.K., Patel D.K. A review on pharmacological and analytical aspects of naringenin. Chin. J. Integr. Med. 2014;24:551-560.

    Not in our library10.1007/s11655-014-1960-x

  37. 37.

    Bao L., Liu F., Guo H.B., Li Y., Tan B.B., Zhang W.X., Peng Y.H. Naringenin inhibits proliferation, migration, and invasion as well as induces apoptosis of gastric cancer sgc7901 cell line by downregulation of akt pathway. Tumor Biol. 2016;37:11365-11374.

    Not in our library10.1007/s13277-016-5013-2

  38. 38.

    Zhang H., Zhong X., Zhang X., Shang D., Zhou Y., Zhang C. Enhanced anticancer effect of abt-737 in combination with naringenin on gastric cancer cells. Exp. Ther. Med. 2016;11:669-673.

    Not in our library10.3892/etm.2015.2912

  39. 39.

    Ahamad M.S., Siddiqui S., Jafri A., Ahmad S., Afzal M., Arshad M. Induction of apoptosis and antiproliferative activity of naringenin in human epidermoid carcinoma cell through ros generation and cell cycle arrest. PLoS ONE. 2014;9:e110003.

    Not in our library10.1371/journal.pone.0110003

  40. 40.

    Arul D., Subramanian P. Naringenin (citrus flavonone) induces growth inhibition, cell cycle arrest and apoptosis in human hepatocellular carcinoma cells. Pathol. Oncol. Res. 2013;19:763-770.

    Not in our library10.1007/s12253-013-9641-1

  41. 41.

    Kapoor R., Rizvi F., Kakkar P. Naringenin prevents high glucose-induced mitochondria-mediated apoptosis involving aif, endo-g and caspases. Apoptosis. 2013;18:9-27.

    Not in our library10.1007/s10495-012-0781-7

  42. 42.

    Bulzomi P., Bolli A., Galluzzo P., Acconcia F., Ascenzi P., Marino M. The naringenin-induced proapoptotic effect in breast cancer cell lines holds out against a high bisphenol a background. IUBMB Life. 2012;64:690-696.

    Not in our library10.1002/iub.1049

  43. 43.

    Krishnakumar N., Sulfikkarali N., RajendraPrasad N., Karthikeyan S. Enhanced anticancer activity of naringenin-loaded nanoparticles in human cervical (hela) cancer cells. Biomed. Prev. Nutr. 2011;1:223-231.

    Not in our library10.1016/j.bionut.2011.09.003

  44. 44.

    Kim J.H., Kang J.W., Kim M.S., Bak Y., Park Y.S., Jung K.Y., Lim Y.H., Yoon D.Y. The apoptotic effects of the flavonoid n101-2 in human cervical cancer cells. Toxicol. In Vitro. 2012;26:67-73.

    Not in our library10.1016/j.tiv.2011.10.012

  45. 45.

    Park H.J., Choi Y.J., Lee J.H., Nam M.J. Naringenin causes ask1-induced apoptosis via reactive oxygen species in human pancreatic cancer cells. Food Chem. Toxicol. 2017;99:1-8.

    Not in our library10.1016/j.fct.2016.11.008

  46. 46.

    Abdulkhaleq L.A., Assi M.A., Noor M.H.M., Abdullah R., Saad M.Z., Taufiq-Yap Y.H. Therapeutic uses of epicatechin in diabetes and cancer. Vet. World. 2017;10:869-872.

    Not in our library10.14202/vetworld.2017.869-872

  47. 47.
    Molecular Mechanisms and Therapeutic Effects of (−)-Epicatechin and Other Polyphenols in Cancer, Inflammation, Diabetes, and Neurodegeneration · 2015
    No notice
  48. 48.

    Amin A., Gali-muhtasib H., Ocker M., Schneider-stock R. Overview of major classes of plant-derived anticancer drugs. Int. J. Biomed. Sci. 2009;5:1-11.

    Not in our library

  49. 49.

    Moradzadeh M., Hosseini A., Erfanian S., Rezaei H. Epigallocatechin-3-gallate promotes apoptosis in human breast cancer t47d cells through down-regulation of pi3k/akt and telomerase. Pharmacol. Rep. 2017;69:924-928.

    Not in our library10.1016/j.pharep.2017.04.008

  50. 50.

    Li M.-J. Green tea compounds in breast cancer prevention and treatment. World J. Clin. Oncol. 2014;5:520.

    Not in our library10.5306/wjco.v5.i3.520

  51. 51.

    Liu L., Hou L., Gu S., Zuo X., Meng D., Luo M., Zhang X., Huang S., Zhao X. Molecular mechanism of epigallocatechin-3-gallate in human esophageal squamous cell carcinoma in vitro and in vivo. Oncol. Rep. 2015;33:297-303.

    Not in our library10.3892/or.2014.3555

  52. 52.

    Cerezo-Guisado M.I., Zur R., Lorenzo M.J., Risco A., Martín-Serrano M.A., Alvarez-Barrientos A., Cuenda A., Centeno F. Implication of akt, erk1/2 and alternative p38mapk signalling pathways in human colon cancer cell apoptosis induced by green tea egcg. Food Chem. Toxicol. 2015;84:125-132.

    Not in our library10.1016/j.fct.2015.08.017

  53. 53.

    Kwak T.W., Park S.B., Kim H.J., Jeong Y.I.L., Kang D.H. Anticancer activities of epigallocatechin-3-gallate against cholangiocarcinoma cells. OncoTargets Ther. 2017;10:137-144.

    Not in our library10.2147/ott.s112364

  54. 54.

    Sonoda J.I., Ikeda R., Baba Y., Narumi K., Kawachi A., Tomishige E., Nishihara K., Takeda Y., Yamada K., Sato K., et al. Green tea catechin, epigallocatechin-3-gallate, attenuates the cell viability of human non-small-cell lung cancer a549 cells via reducing bcl-xl expression. Exp. Ther. Med. 2014;8:59-63.

    Not in our library10.3892/etm.2014.1719

  55. 55.
    In Vitro and in Vivo Antitumoral Effects of Combinations of Polyphenols, or Polyphenols and Anticancer Drugs: Perspectives on Cancer Treatment · 2015
    No notice
  56. 56.

    Gupta S., Hastak K., Afaq F., Ahmad N., Mukhtar H. Essential role of caspases in epigallocatechin-3-gallate-mediated inhibition of nuclear factor kappa b and induction of apoptosis. Oncogene. 2004;23:2507-2522.

    Not in our library10.1038/sj.onc.1207353

  57. 57.

    Pan M.H., Lin C.C., Lin J.K., Chen W.J. Tea polyphenol (-)-epigallocatechin 3-gallate suppresses heregulin-beta1-induced fatty acid synthase expression in human breast cancer cells by inhibiting phosphatidylinositol 3-kinase/akt and mitogen-activated protein kinase cascade signaling. J. Agric. Food Chem. 2007;55:5030-5037.

    Not in our library10.1021/jf070316r

  58. 58.

    Pianetti S., Guo S., Kavanagh K.T., Sonenshein G.E. Green tea polyphenol epigallocatechin-3 gallate inhibits her-2/neu signaling, proliferation, and transformed phenotype of breast cancer cells. Cancer Res. 2002;62:652-655.

    Not in our library

  59. 59.

    Masuda M., Suzui M., Lim J.T., Deguchi A., Soh J.W., Weinstein I.B. Epigallocatechin-3-gallate decreases vegf production in head and neck and breast carcinoma cells by inhibiting egfr-related pathways of signal transduction. J. Exp. Ther. Oncol. 2002;2:350-359.

    Not in our library10.1046/j.1359-4117.2002.01062.x

  60. 60.
    Quercetin Suppresses Twist to Induce Apoptosis in MCF-7 Breast Cancer Cells · 2015
    No notice
  61. 61.

    Damnjanovic I., Najman S., Stojanovic S., Stojanovic D., Veljkovic A., Kocic H., Langerholc T., Damnjanovic Z., Pesic S. Quercetin induces apoptosis and necroptosis in mcf-7 breast cancer cells. Bratislavské Lekárske Listy. 2017;116:227-232.

    Not in our library10.4149/bll_2015_044

  62. 62.

    Zhang L. Quercetin inhibits human breast cancer cell proliferation and induces apoptosis via bcl-2 and bax regulation. Mol. Med. Rep. 2012;1453-1456.

    Not in our library10.3892/mmr.2012.845

  63. 63.

    Chou C.-C., Yang J.-S., Lu H.-F., Ip S.-W., Lo C., Wu C.-C., Lin J.-P., Tang N.-Y., Chung J.-G., Chou M.-J., et al. Quercetin-mediated cell cycle arrest and apoptosis involving activation of a caspase cascade through the mitochondrial pathway in human breast cancer mcf-7 cells. Arch. Pharm. Res. 2010;33:1181-1191.

    Not in our library10.1007/s12272-010-0808-y

  64. 64.

    Seo H.S., Ku J.M., Choi H.S., Choi Y.K., Woo J.K., Kim M., Kim I., Na C.H., Hur H., Jang B.H., et al. Quercetin induces caspase-dependent extrinsic apoptosis through inhibition of signal transducer and activator of transcription 3 signaling in her2-overexpressing bt-474 breast cancer cells. Oncol. Rep. 2016;36:31-42.

    Not in our library10.3892/or.2016.4786

  65. 65.

    Niu G., Yin S., Xie S., Li Y., Nie D., Ma L., Wang X., Wu Y. Quercetin induces apoptosis by activating caspase-3 and regulating bcl-2 and cyclooxygenase-2 pathways in human hl-60 cells. Acta Biochim. Biophys. Sin. 2011;43:30-37.

    Not in our library10.1093/abbs/gmq107

  66. 66.

    Granato M., Rizzello C., Montani M.S.G., Cuomo L., Vitillo M., Santarelli R., Gonnella R., D’Orazi G., Faggioni A., Cirone M. Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting pi3k/akt/mtor and stat3 signaling pathways. J. Nutr. Biochem. 2017;41:124-136.

    Not in our library10.1016/j.jnutbio.2016.12.011

  67. 67.

    Wang P., Heber D., Henning S.M. Quercetin increased the antiproliferative activity of green tea polyphenol (-)-epigallocatechin gallate in prostate cancer cells. Nutr. Cancer. 2012;64:580-587.

    Not in our library10.1080/01635581.2012.661514

  68. 68.

    Sun S., Gong F., Liu P., Miao Q. Metformin combined with quercetin synergistically repressed prostate cancer cells via inhibition of vegf/pi3k/akt signaling pathway. Gene. 2018;664:50-57.

    Not in our library10.1016/j.gene.2018.04.045

  69. 69.

    Jeong J.H., An J.Y., Kwon Y.T., Li L.Y., Lee Y.J. Quercetin-induced ubiquitination and down-regulation of her-2/neu. J. Cell. Biochem. 2008;105:585-595.

    Not in our library10.1002/jcb.21859

  70. 70.

    Granado-Serrano A.B., Martin M.A., Bravo L., Goya L., Ramos S. Quercetin modulates nf-kappa b and ap-1/jnk pathways to induce cell death in human hepatoma cells. Nutr. Cancer. 2010;62:390-401.

    Not in our library10.1080/01635580903441196

  71. 71.

    Calder M., Burgos E. A review on the dietary flavonoid kaempferol. Mini Rev. Med. Chem. 2011;11:298-344.

    Not in our library10.2174/138955711795305335

  72. 72.

    Chen A.Y., Chen Y.C. A review of the dietary flavonoid, kaempferol on human health and cancer chemoprevention. Food Chem. 2013;138:2099-2107.

    Not in our library10.1016/j.foodchem.2012.11.139

  73. 73.

    Kim S.H., Choi K.C. Anti-cancer effect and underlying mechanism(s) of kaempferol, a phytoestrogen, on the regulation of apoptosis in diverse cancer cell models. Toxicol. Res. 2013;29:229-234.

    Not in our library10.5487/tr.2013.29.4.229

  74. 74.

    Luo H., Jiang B., Li B., Li Z., Jiang B.H., Chen Y.C. Kaempferol nanoparticles achieve strong and selective inhibition of ovarian cancer cell viability. Int. J. Nanomed. 2012;7:3951-3959.

    Not in our library10.2147/ijn.s33670

  75. 75.

    Li W., Du B., Wang T., Wang S., Zhang J. Kaempferol induces apoptosis in human hct116 colon cancer cells via the ataxia-telangiectasia mutated-p53 pathway with the involvement of p53 upregulated modulator of apoptosis. Chem.-Biol. Interact. 2009;177:121-127.

    Not in our library10.1016/j.cbi.2008.10.048

  76. 76.

    Luo H., Rankin G.O., Li Z., DePriest L., Chen Y.C. Kaempferol induces apoptosis in ovarian cancer cells through activating p53 in the intrinsic pathway. Food Chem. 2011;128:513-519.

    Not in our library10.1016/j.foodchem.2011.03.073

  77. 77.

    Moradzadeh M., Tabarraei A., Sadeghnia H.R., Ghorbani A., Mohamadkhani A., Erfanian S., Sahebkar A. Kaempferol increases apoptosis in human acute promyelocytic leukemia cells and inhibits multidrug resistance genes. J. Cell. Biochem. 2018;119:2288-2297.

    Not in our library10.1002/jcb.26391

  78. 78.

    Luo H., Daddysman M.K., Rankin G.O., Jiang B.H., Chen Y.C. Kaempferol enhances cisplatin’s effect on ovarian cancer cells through promoting apoptosis caused by down regulation of cmyc. Cancer Cell Int. 2010;10:1-9.

    Not in our library10.1186/1475-2867-10-16

  79. 79.

    Guo H., Ren F., Zhang L.I., Zhang X., Yang R. Kaempferol induces apoptosis in hepg2 cells via activation of the endoplasmic reticulum stress pathway. Mol. Med. Rep. 2016;13:2791-2800.

    Not in our library10.3892/mmr.2016.4845

  80. 80.

    Jeong J.C., Kim M.S., Kim T.H., Kim Y.K. Kaempferol induces cell death through erk and akt-dependent down-regulation of xiap and survivin in human glioma cells. Neurochem. Res. 2009;34:991-1001.

    Not in our library10.1007/s11064-008-9868-5

  81. 81.

    Kashafi E., Moradzadeh M., Mohamadkhani A., Erfanian S. Kaempferol increases apoptosis in human cervical cancer hela cells via pi3k/akt and telomerase pathways. Biomed. Pharmacother. 2017;89:573-577.

    Not in our library10.1016/j.biopha.2017.02.061

  82. 82.

    Khan N., Syed D.N., Ahmad N., Mukhtar H. Fisetin: A dietary antioxidant for health promotion. Antioxid. Redox Signal. 2013;19:151-162.

    Not in our library10.1089/ars.2012.4901

  83. 83.

    Khan N., Afaq F., Syed D.N. Fisetin, a novel dietary flavonoid, causes apoptosis and cell cycle arrest in human prostate cancer lncap cells. Carcinogenesis. 2018;29:1049-1056.

    Not in our library10.1093/carcin/bgn078

  84. 84.

    Szliszka E., Helewski K.J., Mizgala E., Krol W. The dietary flavonol fisetin enhances the apoptosis-inducing potential of trail in prostate cancer cells. Int. J. Oncol. 2011;39:771-779.

    Not in our library10.3892/ijo.2011.1116

  85. 85.

    Sabarwal A., Agarwal R., Singh R.P. Fisetin inhibits cellular proliferation and induces mitochondria-dependent apoptosis in human gastric cancer cells. Mol. Carcinogen. 2017;514:499-514.

    Not in our library10.1002/mc.22512

  86. 86.

    Lin M.-T., Lin C.-L., Lin T.-Y., Cheng C.-W., Yang S.-F., Lin C.-L., Wu C.-C., Hsieh Y.-H., Tsai J.-P. Synergistic effect of fisetin combined with sorafenib in human cervical cancer hela cells through activation of death receptor-5 mediated caspase-8/caspase-3 and the mitochondria-dependent apoptotic pathway. Tumor Biol. 2015;60:1396-1405.

    Not in our library10.1007/s13277-015-4526-4

  87. 87.

    Ying T.H., Yang S.F., Tsai S.J., Hsieh S.C., Huang Y.C., Bau D.T., Hsieh Y.H. Fisetin induces apoptosis in human cervical cancer hela cells through erk1/2-mediated activation of caspase-8-/caspase-3-dependent pathway. Arch Toxicol. 2012;86:263-273.

    Not in our library10.1007/s00204-011-0754-6

  88. 88.

    Kang K.A., Piao M.J., Ruwan S., Madduma K. Fisetin induces apoptosis and endoplasmic reticulum stress in human non-small cell lung cancer through inhibition of the mapk signaling pathway. Tumor Biol. 2016;37:9615-9624.

    Not in our library10.1007/s13277-016-4864-x

  89. 89.

    Yi C., Zhang Y., Yu Z., Xiao Y., Wang J., Qiu H., Yu W., Tang R., Yuan Y., Guo W., et al. Melatonin enhances the anti-tumor effect of fisetin by inhibiting cox-2/inos and nf-kb/p300 signaling pathways. PLoS ONE. 2014;9:e99943.

    Not in our library10.1371/journal.pone.0099943

  90. 90.

    Young K., Jeong S.-J., Kim S.-H., Hoon J., Kim J.-H., Koh W., Chen C.-Y., Kim S.-H. Activation of reactive oxygen species/amp activated protein kinase signaling mediates fisetin-induced apoptosis in multiple myeloma u266 cells. Cancer Lett. 2012;319:197-202.

    Not in our library10.1016/j.canlet.2012.01.008

  91. 91.

    Devi K.P., Rajavel T., Habtemariam S., Nabavi S.F., Nabavi S.M. Molecular mechanisms underlying anticancer effects of myricetin. Life Sci. 2015;142:19-25.

    Not in our library10.1016/j.lfs.2015.10.004

  92. 92.

    Kim M.E., Ha T.K., Yoon J.H., Lee J.S. Myricetin induces cell death of human colon cancer cells. Anticancer Res. 2014;34:701-706.

    Not in our library

  93. 93.

    Kim W., Yang H.J., Youn H., Yun Y.J., Seong K.M., Youn B. Myricetin inhibits akt survival signaling and induces bad-mediated apoptosis in a low dose ultraviolet (uv)-b-irradiated hacat human immortalized keratinocytes. J. Radiat. Res. 2010;51:285-296.

    Not in our library10.1269/jrr.09141

  94. 94.

    Xu Y., Xie Q., Wu S., Yi D., Yu Y., Liu S., Li S., Li Z. Myricetin induces apoptosis via endoplasmic reticulum stress and DNA double-strand breaks in human ovarian cancer cells. Mol. Med. Rep. 2016;13:2094-2100.

    Not in our library10.3892/mmr.2016.4763

  95. 95.

    Huang H., Chen A.Y., Ye X., Li B., Rojanasakul Y., Rankin G.O., Chen Y.C. Myricetin inhibits proliferation of cisplatin-resistant cancer cells through a p53-dependent apoptotic pathway. Int. J. Oncol. 2015;47:1494-1502.

    Not in our library10.3892/ijo.2015.3133

  96. 96.

    Knickle A., Fernando W., Greenshields A.L., Rupasinghe H.P.V., Hoskin D.W. Myricetin-induced apoptosis of triple-negative breast cancer cells is mediated by the iron-dependent generation of reactive oxygen species from hydrogen peroxide. Food Chem. Toxicol. 2018;118:154-167.

    Not in our library10.1016/j.fct.2018.05.005

  97. 97.

    Lirdprapamongkol K., Sakurai H., Abdelhamed S., Yokoyama S., Athikomkulchai S., Viriyaroj A., Awale S., Ruchirawat S., Svasti J., Saiki I. Chrysin overcomes trail resistance of cancer cells through mcl-1 downregulation by inhibiting stat3 phosphorylation. Int. J. Oncol. 2013;43:329-337.

    Not in our library10.3892/ijo.2013.1926

  98. 98.

    Kim D.A., Jeon Y.K., Nam M.J. Galangin induces apoptosis in gastric cancer cells via regulation of ubiquitin carboxy-terminal hydrolase isozyme l1 and glutathione s-transferase p. Food Chem. Toxicol. 2012;50:684-688.

    Not in our library10.1016/j.fct.2011.11.039

  99. 99.

    Zhang H.-T. Galangin induces apoptosis of hepatocellular carcinoma cells via the mitochondrial pathway. World J. Gastroenterol. 2010;16:3377.

    Not in our library10.3748/wjg.v16.i27.3377

  100. 100.

    Zhang H.T., Wu J., Wen M., Su L.J., Luo H. Galangin induces apoptosis in hepatocellular carcinoma cells through the caspase 8/t-bid mitochondrial pathway. J. Asian Nat. Prod. Res. 2012;14:626-633.

    Not in our library10.1080/10286020.2012.682152

  101. 101.

    Zhang W., Lan Y., Huang Q., Hua Z. Galangin induces b16f10 melanoma cell apoptosis via mitochondrial pathway and sustained activation of p38 mapk. Cytotechnology. 2013;65:447-455.

    Not in our library10.1007/s10616-012-9499-1

  102. 102.

    Ren K., Zhang W., Wu G., Ren J., Lu H., Li Z., Han X. Synergistic anti-cancer effects of galangin and berberine through apoptosis induction and proliferation inhibition in oesophageal carcinoma cells. Biomed. Pharmacother. 2016;84:1748-1759.

    Not in our library10.1016/j.biopha.2016.10.111

  103. 103.

    Rasul A., Zhao B.J., Liu J., Liu B., Sun J.X., Li J., Li X.M. Molecular mechanisms of casticin action: An update on its antitumor functions. Asian Pac. J. Cancer Prev. 2014;15:9049-9058.

    Not in our library10.7314/apjcp.2014.15.21.9049

  104. 104.

    Chan E.W.C., Wong S.K., Chan H.T. Casticin from vitex species: A short review on its anticancer and anti-inflammatory properties. J. Integr. Med. 2018;16:147-152.

    Not in our library10.1016/j.joim.2018.03.001

  105. 105.

    Zhou Y., Peng Y., Mao Q.Q., Li X., Chen M.W., Su J., Tian L., Mao N.Q., Long L.Z., Quan M.F., et al. Casticin induces caspase-mediated apoptosis via activation of mitochondrial pathway and upregulation of dr5 in human lung cancer cells. Asian Pac. J. Trop. Med. 2013;6:372-378.

    Not in our library10.1016/s1995-7645(13)60041-3

  106. 106.

    Zhou Y., Tian L., Long L., Quan M., Liu F., Cao J. Casticin potentiates trail-induced apoptosis of gastric cancer cells through endoplasmic reticulum stress. PLoS ONE. 2013;8:e58855.

    Not in our library10.1371/journal.pone.0058855

  107. 107.

    Ding C., Khan M., Zheng B., Yang J., Zhong L., Ma T. Casticin induces apoptosis and mitotic arrest in pancreatic carcinoma panc-1 cells. Afr. J. Pharm. Pharmacol. 2012;6:412-418.

    Not in our library

  108. 108.

    Meng F.-M., Yang J.-B., Yang C.-H., Jiang Y., Zhou Y.-F., Yu B., Yang H. Vitexicarpin induces apoptosis in human prostate carcinoma pc-3 cells through g2/m phase arrest. Asian Pac. J. Cancer Prev. 2012;13:6369-6374.

    Not in our library10.7314/apjcp.2012.13.12.6369

  109. 109.

    Chonghao W. Vitexicarpin induces apoptosis-independent mitotic arrest in u87 glioblastoma cells. Afr. J. Pharm. Pharmacol. 2012;6:1874-1882.

    Not in our library10.5897/ajpp12.378

  110. 110.

    Liu E., Kuang Y., He W., Xing X., Gu J. Casticin induces human glioma cell death through apoptosis and mitotic arrest. Cell. Physiol. Biochem. 2013;31:805-814.

    Not in our library10.1159/000350098

  111. 111.

    Song X.-L., Zhang Y.-J., Wang X.-F., Zhang W.-J., Wang Z., Zhang F., Zhang Y.-J., Lu J.-H., Mei J.-W., Hu Y.-P., et al. Casticin induces apoptosis and g0/g1 cell cycle arrest in gallbladder cancer cells. Cancer Cell Int. 2017;17:9.

    Not in our library10.1186/s12935-016-0377-3

  112. 112.

    Mason A. Plant flavone apigenin inhibits hdac and remodels chromatin to induce growth arrest and apoptosis in human prostate cancer cells: In vitro and in vivo study. Mol. Carcinogen. 2012;51:952-962.

    Not in our library10.1002/mc.20866

  113. 113.

    Shukla S., Fu P., Gupta S. Apigenin induces apoptosis by targeting inhibitor of apoptosis proteins and ku70-bax interaction in prostate cancer. Apoptosis. 2014;19:883-894.

    Not in our library10.1007/s10495-014-0971-6

  114. 114.

    Chan L.P., Chou T.H., Ding H.Y., Chen P.R., Chiang F.Y., Kuo P.L., Liang C.H. Apigenin induces apoptosis via tumor necrosis factor receptor- and bcl-2-mediated pathway and enhances susceptibility of head and neck squamous cell carcinoma to 5-fluorouracil and cisplatin. Biochim. Biophys. Acta Gen. Subj. 2012;1820:1081-1091.

    Not in our library10.1016/j.bbagen.2012.04.013

  115. 115.

    Meng S., Zhu Y., Li J.-F., Wang X., Liang Z., Li S.-Q., Xu X. Apigenin inhibits renal cell carcinoma cell proliferation. Oncotarget. 2017;8:19834-19842.

    Not in our library10.18632/oncotarget.15771

  116. 116.

    Shi M.D., Shiao C.K., Lee Y.C., Shih Y.W. Apigenin, a dietary flavonoid, inhibits proliferation of human bladder cancer T-24 cells via blocking cell cycle progression and inducing apoptosis. Cancer Cell Int. 2015;15:1-12.

    Not in our library10.1186/s12935-015-0186-0

  117. 117.

    Zhu Y., Mao Y.Q., Chen H., Lin Y.W., Hu Z.H., Wu J., Xu X., Xu X.L., Qin J., Xie L.P. Apigenin promotes apoptosis, inhibits invasion and induces cell cycle arrest of t24 human bladder cancer cells. Cancer Cell Int. 2013;13:1-7.

    Not in our library10.1186/1475-2867-13-54

  118. 118.

    Wang Q.R., Yao X.Q., Wen G., Fan Q., Li Y.J., Fu X.Q., Li C.K., Sun X.G. Apigenin suppresses the growth of colorectal cancer xenografts via phosphorylation and up-regulated fadd expression. Oncol. Lett. 2011;2:43-47.

    Not in our library10.3892/ol.2010.215

  119. 119.

    Zhang L., Cheng X., Gao Y., Zheng J., Xu Q., Sun Y., Guan H., Yu H., Sun Z. Apigenin induces autophagic cell death in human papillary thyroid carcinoma bcpap cells. Food Funct. 2015;6:3464-3472.

    Not in our library10.1039/c5fo00671f

  120. 120.

    Liu R., Ji P., Liu B., Qiao H., Wang X., Zhou L., Deng T., Ba Y. Apigenin enhances the cisplatin cytotoxic effect through p53-modulated apoptosis. Oncol. Lett. 2017;13:1024-1030.

    Not in our library10.3892/ol.2016.5495

  121. 121.

    Masuelli L., Marzocchella L., Quaranta A., Palumbo C., Pompa G., Izzi V., Canini A., Modesti A., Galvano F., Bei R. Apigenin induces apoptosis and impairs head and neck carcinomas egfr/erbb2 signaling. Front. Biosci. 2011;16:1060-1068.

    Not in our library10.2741/3735

  122. 122.

    Masuelli L., Benvenuto M., Mattera R., Di Stefano E., Zago E., Taffera G., Tresoldi I., Giganti M.G., Frajese G.V., Berardi G., et al. In vitro and in vivo anti-tumoral effects of the flavonoid apigenin in malignant mesothelioma. Front. Pharmacol. 2017;8:373.

    Not in our library10.3389/fphar.2017.00373

  123. 123.

    Shukla S., Gupta S. Apigenin-induced cell cycle arrest is mediated by modulation of mapk, pi3k-akt, and loss of cyclin d1 associated retinoblastoma dephosphorylation in human prostate cancer cells. Cell Cycle. 2007;6:1102-1114.

    Not in our library10.4161/cc.6.9.4146

  124. 124.

    Mehdi S.H., Nafees S., Khan A., Rizvi M.A. Chrysin: A promising anticancer agent its current trends and future imedpub journals chrysin: A promising anticancer agent its current trends and future perspectives. Eur. J. Exp. Biol. 2018;8:16.

    Not in our library10.21767/2248-9215.100057

  125. 125.

    Kasala E.R., Bodduluru L.N., Madana R.M., Athira K.V., Gogoi R., Barua C.C. Chemopreventive and Therapeutic Potential of Chrysin in Cancer: Mechanistic Perspectives. 2015;Volume 233:214-225.

    Not in our library10.1016/j.toxlet.2015.01.008

  126. 126.
    Apoptotic Effects of Chrysin in Human Cancer Cell Lines · 2010
    No notice
  127. 127.

    Li X., Wang J.N., Huang J.M., Xiong X.K., Chen M.F., Ong C.N., Shen H.M., Yang X.F. Chrysin promotes tumor necrosis factor (tnf)-related apoptosis-inducing ligand (trail) induced apoptosis in human cancer cell lines. Toxicol. In Vitro. 2011;25:630-635.

    Not in our library10.1016/j.tiv.2010.12.013

  128. 128.

    Ryu S., Lim W., Bazer F.W., Song G. Chrysin induces death of prostate cancer cells by inducing ros and er stress. J. Cell. Physiol. 2017;232:3786-3797.

    Not in our library10.1002/jcp.25861

  129. 129.

    Xue C., Chen Y., Hu D.N., Iacob C., Lu C., Huang Z. Chrysin induces cell apoptosis in human uveal melanoma cells via intrinsic apoptosis. Oncol. Lett. 2016;4813-4820.

    Not in our library10.3892/ol.2016.5251

  130. 130.

    Li X., Huang J.M., Wang J.N., Xiong X.K., Yang X.F., Zou F. Combination of chrysin and cisplatin promotes the apoptosis of hep g2 cells by up-regulating p53. Chem.-Biol. Interact. 2015;232:12-20.

    Not in our library10.1016/j.cbi.2015.03.003

  131. 131.

    Zhang Q., Ma S., Liu B., Liu J., Zhu R., Li M. Chrysin induces cell apoptosis via activation of the p53/bcl-2/caspase-9 pathway in hepatocellular carcinoma cells. Exp. Ther. Med. 2016;12:469-474.

    Not in our library10.3892/etm.2016.3282

  132. 132.

    Chen Z., Kong S., Song F., Li L., Jiang H. Pharmacokinetic study of luteolin, apigenin, chrysoeriol and diosmetin after oral administration of flos chrysanthemi extract in rats. Fitoterapia. 2012;83:1616-1622.

    Not in our library10.1016/j.fitote.2012.09.011

  133. 133.

    Tuorkey M.J. Molecular targets of luteolin in cancer. Eur. J. Cancer Prev. 2016;25:65-76.

    Not in our library10.1097/cej.0000000000000128

  134. 134.

    Hwang J.T., Park O.J., Lee Y.K., Sung M.J., Hur H.J., Kim M.S., Ha J.H., Kwon D.Y. Anti-tumor effect of luteolin is accompanied by amp-activated protein kinase and nuclear factor-κb modulation in hepg2 hepatocarcinoma cells. Int. J. Mol. Med. 2011;28:25-31.

    Not in our library10.3892/ijmm.2011.667

  135. 135.

    Lee H.J., Wang C.J., Kuo H.C., Chou F.P., Jean L.F., Tseng T.H. Induction apoptosis of luteolin in human hepatoma hepg2 cells involving mitochondria translocation of bax/bak and activation of jnk. Toxicol. Appl. Pharmacol. 2005;203:124-131.

    Not in our library10.1016/j.taap.2004.08.004

  136. 136.

    Cai X., Ye T., Liu C., Lu W., Lu M., Zhang J., Wang M., Cao P. Luteolin induced g2 phase cell cycle arrest and apoptosis on non-small cell lung cancer cells. Toxicol. In Vitro. 2011;25:1385-1391.

    Not in our library10.1016/j.tiv.2011.05.009

  137. 137.

    Jiang Z.-Q., Li M.-H., Qin Y.-M., Jiang H.-Y., Zhang X., Wu M.-H. Luteolin inhibits tumorigenesis and induces apoptosis of non-small cell lung cancer cells via regulation of microrna-34a-5p. Int. J. Mol. Sci. 2018;19:447.

    Not in our library10.3390/ijms19020447

  138. 138.

    Yang S.F., Yang W.E., Chang H.R., Chu S.C., Hsieh Y.S. Luteolin induces apoptosis in oral squamous cancer cells. J. Dent. Res. 2008;87:401-406.

    Not in our library10.1177/154405910808700413

  139. 139.

    Park S.H., Park H.S., Lee J.H., Chi G.Y., Kim G.Y., Moon S.K., Chang Y.C., Hyun J.W., Kim W.J., Choi Y.H. Induction of endoplasmic reticulum stress-mediated apoptosis and non-canonical autophagy by luteolin in nci-h460 lung carcinoma cells. Food Chem. Toxicol. 2013;56:100-109.

    Not in our library10.1016/j.fct.2013.02.022

  140. 140.

    Wang Q., Wang H., Jia Y., Pan H., Ding H. Luteolin induces apoptosis by ros/er stress and mitochondrial dysfunction in gliomablastoma. Cancer Chemother. Pharmacol. 2017;79:1031-1041.

    Not in our library10.1007/s00280-017-3299-4

  141. 141.

    Johnson J.L., Gonzalez de Mejia E. Interactions between dietary flavonoids apigenin or luteolin and chemotherapeutic drugs to potentiate anti-proliferative effect on human pancreatic cancer cells, in vitro. Food Chem. Toxicol. 2013;60:83-91.

    Not in our library10.1016/j.fct.2013.07.036

  142. 142.

    Yang M.Y., Wang C.J., Chen N.F., Ho W.H., Lu F.J., Tseng T.H. Luteolin enhances paclitaxel-induced apoptosis in human breast cancer mda-mb-231 cells by blocking stat3. Chem.-Biol. Interact. 2014;213:60-68.

    Not in our library10.1016/j.cbi.2014.02.002

  143. 143.

    Cook M.T., Liang Y., Besch-Williford C., Hyder S.M. Luteolin inhibits lung metastasis, cell migration, and viability of triple-negative breast cancer cells. Breast Cancer Targets Ther. 2016;9:9-19.

    Not in our library10.2147/bctt.s124860

  144. 144.

    Ham S., Kim K.H., Kwon T.H., Bak Y., Lee D.H., Song Y.S., Park S.H., Park Y.S., Kim M.S., Kang J.W., et al. Luteolin induces intrinsic apoptosis via inhibition of e6/e7 oncogenes and activation of extrinsic and intrinsic signaling pathways in hpv-18-associated cells. Oncol. Rep. 2014;31:2683-2691.

    Not in our library10.3892/or.2014.3157

  145. 145.

    Bo W., Zhao X.H. Apigenin induces both intrinsic and extrinsic pathways of apoptosis in human colon carcinoma hct-116 cells. Oncol. Rep. 2017;37:1132-1140.

    Not in our library10.3892/or.2016.5303

  146. 146.

    Chen H., Gao Y., Wu J., Chen Y., Chen B., Hu J., Zhou J. Exploring therapeutic potentials of baicalin and its aglycone baicalein for hematological malignancies. Cancer Lett. 2014;354:5-11.

    Not in our library10.1016/j.canlet.2014.08.003

  147. 147.

    Gao Y., Snyder S.A., Smith J.N., Chen Y.C. Anticancer properties of baicalein: A review. Med. Chem. Res. 2016;25:1515-1523.

    Not in our library10.1007/s00044-016-1607-x

  148. 148.

    Takahashi H., Chen M.C., Pham H., Angst E., King J.C., Park J., Brovman E.Y., Ishiguro H., Harris D.M., Reber H.A., et al. Baicalein, a component of scutellaria baicalensis, induces apoptosis by mcl-1 down-regulation in human pancreatic cancer cells. Biochim. Biophys. Acta Mol. Cell Res. 2011;1813:1465-1474.

    Not in our library10.1016/j.bbamcr.2011.05.003

  149. 149.

    Zhou R.-T., He M., Yu Z., Liang Y., Nie Y., Tai S., Teng C.-B. Baicalein inhibits pancreatic cancer cell proliferation and invasion via suppression of nedd9 expression and its downstream akt and erk signaling pathways. Oncotarget. 2017;8:56351-56363.

    Not in our library10.18632/oncotarget.16912

  150. 150.

    Chai Y., Xu J., Yan B. The anti-metastatic effect of baicalein on colorectal cancer. Oncol. Rep. 2017;37:2317-2323.

    Not in our library10.3892/or.2017.5437

  151. 151.

    Kim S.J., Kim H.J., Kim H.R., Lee S.H., Cho S.D., Choi C.S., Nam J.S., Jung J.Y. Antitumor actions of baicalein and wogonin in ht-29 human colorectal cancer cells. Mol. Med. Rep. 2012;6:1443-1449.

    Not in our library10.3892/mmr.2012.1085

  152. 152.

    Mu J., Liu T., Jiang L., Wu X., Cao Y., Li M., Dong Q., Liu Y., Xu H. The traditional chinese medicine baicalein potently inhibits gastric cancer cells. J. Cancer. 2016;7:453-461.

    Not in our library10.7150/jca.13548

  153. 153.
    The Fascinating Effects of Baicalein on Cancer: A Review · 2016
    No notice
  154. 154.

    Peng Y., Guo C., Yang Y., Li F., Zhang Y., Jiang B., Li Q. Baicalein induces apoptosis of human cervical cancer hela cells in vitro. Mol. Med. Rep. 2015;11:2129-2134.

    Not in our library10.3892/mmr.2014.2885

  155. 155.

    Wang Z., Jiang C., Chen W., Zhang G., Luo D., Cao Y., Wu J., Ding Y., Liu B. Baicalein induces apoptosis and autophagy via endoplasmic reticulum stress in hepatocellular carcinoma cells. Biomed. Res. Int. 2014;2014:732516.

    Not in our library10.1155/2014/732516

  156. 156.

    Cirmi S., Ferlazzo N., Lombardo G.E., Maugeri A., Calapai G., Gangemi S., Navarra M. Chemopreventive agents and inhibitors of cancer hallmarks: May citrus offer new perspectives? Nutrients. 2016;8:698.

    Not in our library10.3390/nu8110698

  157. 157.

    Periyasamy K., Baskaran K., Ilakkia A., Vanitha K., Selvaraj S., Sakthisekaran D. Antitumor efficacy of tangeretin by targeting the oxidative stress mediated on 7,12-dimethylbenz(a) anthracene-induced proliferative breast cancer in sprague-dawley rats. Cancer Chemother. Pharmacol. 2015;75:263-272.

    Not in our library10.1007/s00280-014-2629-z

  158. 158.

    Arivazhagan L., Sorimuthu Pillai S. Tangeretin, a citrus pentamethoxyflavone, exerts cytostatic effect via p53/p21 up-regulation and suppresses metastasis in 7,12-dimethylbenz(α)anthracene-induced rat mammary carcinoma. J. Nutr. Biochem. 2014;25:1140-1153.

    Not in our library10.1016/j.jnutbio.2014.06.007

  159. 159.

    Dong Y., Cao A., Shi J., Yin P., Wang L., Ji G., Xie J., Wu D. Tangeretin, a citrus polymethoxyflavonoid, induces apoptosis of human gastric cancer ags cells through extrinsic and intrinsic signaling pathways. Oncol. Rep. 2014;31:1788-1794.

    Not in our library10.3892/or.2014.3034

  160. 160.

    Ma L.L., Wang D.W., Yu X.D., Zhou Y.L. Tangeretin induces cell cycle arrest and apoptosis through upregulation of pten expression in glioma cells. Biomed. Pharmacother. 2016;81:491-496.

    Not in our library10.1016/j.biopha.2016.04.006

  161. 161.

    Liu X., Chen L., Liu Y., Zhang T. Tangeretin sensitises human lung cancer cells to trail-induced apoptosis via ros-jnk/erk-chop pathway-mediated up-regulation of death receptor 5. Trop. J. Pharm. Res. 2017;16:17-29.

    Not in our library10.4314/tjpr.v16i1.4

  162. 162.

    Kim C.D., Cha J.D., Li S., Cha I.H. The mechanism of acacetin-induced apoptosis on oral squamous cell carcinoma. Arch. Oral Biol. 2015;60:1283-1298.

    Not in our library10.1016/j.archoralbio.2015.05.009

  163. 163.

    Kim H.R., Park C.G., Jung J.Y. Acacetin (5,7-dihydroxy-4′-methoxyflavone) exhibits in vitro and in vivo anticancer activity through the suppression of nf-kb/akt signaling in prostate cancer cells. Int. J. Mol. Med. 2014;33:317-324.

    Not in our library10.3892/ijmm.2013.1571

  164. 164.

    Yomogida S. Acacetin induces apoptosis in human t cell leukemia jurkat cells via activation of a caspase cascade. Oncol. Rep. 2011;204-209.

    Not in our library10.3892/or.2011.1498

  165. 165.

    Salimi A., Roudkenar M.H., Sadeghi L., Mohseni A., Seydi E., Pirahmadi N., Pourahmad J. Selective anticancer activity of acacetin against chronic lymphocytic leukemia using both in vivo and in vitro methods: Key role of oxidative stress and cancerous mitochondria. Nutr. Cancer. 2016;68:1404-1416.

    Not in our library10.1080/01635581.2016.1235717

  166. 166.

    Shen K.-H., Hung S.-H., Yin L.-T., Huang C.-S., Chao C.-H., Liu C.-L., Shih Y.-W. Acacetin, a flavonoid, inhibits the invasion and migration of human prostate cancer du145 cells via inactivation of the p38 mapk signaling pathway. Mol. Cell. Biochem. 2010;333:279-291.

    Not in our library10.1007/s11010-009-0229-8

  167. 167.

    Shim H.-Y., Park J.-H., Paik H.-D., Nah S.-Y., Kim D.S.H.L., Han Y.S. Molecules and acacetin-induced apoptosis of human breast cancer mcf-7 cells involves caspase cascade, mitochondria-mediated death signaling and sapk/jnk1/2-c-jun activation. Mol. Cells. 2007;24:95-104.

    Not in our library

  168. 168.

    Ni W., Ji J., Dai Z., Papp A., Johnson A.J., Ahn S., Farley K.L., Lin T.S., Dalton J.T., Li X., et al. Flavopiridol pharmacogenetics: Clinical and functional evidence for the role of slco1b1/oatp1b1 in flavopiridol disposition. PLoS ONE. 2010;5:e13792.

    Not in our library10.1371/journal.pone.0013792

  169. 169.

    Li L., Pongtornpipat P., Tiutan T., Kendrick S.L., Park S., Persky D.O., Rimsza L.M., Puvvada S.D., Schatz J.H. Synergistic induction of apoptosis in high-risk dlbcl by bcl2 inhibition with abt-199 combined with pharmacologic loss of mcl1. Leukemia. 2015;29:1702-1712.

    Not in our library10.1038/leu.2015.99

  170. 170.

    Mahoney E., Lucas D.M., Gupta S.V., Wagner A.J., Herman S.E.M., Smith L.L., Yeh Y.-Y., Andritsos L., Jones J.A., Flynn J.M., et al. Er stress and autophagy: New players in the mechanism of action and drug resistance of the cyclin-dependent kinase inhibitor flavopiridol. Blood. 2012;120:1262-1273.

    Not in our library10.1182/blood-2011-12-400184

  171. 171.

    Wiernik P.H. Alvocidib (flavopiridol) for the treatment of chronic lymphocytic leukemia. Expert Opin. Investig. Drugs. 2016;25:729-734.

    Not in our library10.1517/13543784.2016.1169273

  172. 172.

    Zhang H.P., Li G.Q., Zhang Y., Guo W.Z., Zhang J.K., Li J., Lv J.F., Zhang S.J. Upregulation of mcl-1 inhibits jq1-triggered anticancer activity in hepatocellular carcinoma cells. Biochem. Biophys. Res. Commun. 2018;495:2456-2461.

    Not in our library10.1016/j.bbrc.2017.12.153

  173. 173.

    Kwak M.S., Yu S.J., Yoon J.H., Lee S.H., Lee S.M., Lee J.H., Kim Y.J., Lee H.S., Kim C.Y. Synergistic anti-tumor efficacy of doxorubicin and flavopiridol in an in vivo hepatocellular carcinoma model. J. Cancer Res. Clin. Oncol. 2015;141:2037-2045.

    Not in our library10.1007/s00432-015-1990-6

  174. 174.

    Gokce O., Dogan Turacli I., Ilke Onen H., Erdem O., Erguven Kayaa E., Ekmekci A. Flavopiridol induces apoptosis via mitochondrial pathway in b16f10 murine melanoma cells and a subcutaneous melanoma tumor model. Acta Dermatovenerol. Croat. 2016;24:2-12.

    Not in our library

  175. 175.

    Zocchi L., Wu S.C., Wu J., Hayama K.L., Benavente C.A. The cyclin-dependent kinase inhibitor flavopiridol (alvocidib) inhibits metastasis of human osteosarcoma cells. Oncotarget. 2018;9:23505-23518.

    Not in our library10.18632/oncotarget.25239

  176. 176.

    Huynh D.L., Sharma N., Kumar Singh A., Singh Sodhi S., Zhang J.J., Mongre R.K., Ghosh M., Kim N., Ho Park Y., Kee Jeong D. Anti-tumor activity of wogonin, an extract from scutellaria baicalensis, through regulating different signaling pathways. Chin. J. Nat. Med. 2017;15:15-40.

    Not in our library10.1016/s1875-5364(17)30005-5

  177. 177.

    Ge W., Yin Q., Xian H. Wogonin induced mitochondrial dysfunction and endoplasmic reticulum stress in human malignant neuroblastoma cells via ire1α-dependent pathway. J. Mol. Neurosci. 2015;56:652-662.

    Not in our library10.1007/s12031-015-0530-9

  178. 178.

    He F., Wang Q., Zheng X.L., Yan J.Q., Yang L., Sun H., Hu L.N., Lin Y., Wang X. Wogonin potentiates cisplatin-induced cancer cell apoptosis through accumulation of intracellular reactive oxygen species. Oncol. Rep. 2012;28:601-605.

    Not in our library10.3892/or.2012.1841

  179. 179.

    Ruibin J., Bo J., Danying W., Chihong Z., Jianguo F., Linhui G. Therapy effects of wogonin on ovarian cancer cells. BioMed Res. Int. 2017;2017:9381513.

    Not in our library10.1155/2017/9381513

  180. 180.

    Xu M., Lu N., Zhang H., Dai Q., Wei L., Li Z., You Q., Guo Q. Wogonin induced cytotoxicity in human hepatocellular carcinoma cells by activation of unfolded protein response and inactivation of akt. Hepatol. Res. 2013;43:890-905.

    Not in our library10.1111/hepr.12036

  181. 181.

    Li S.-J., Sun S.-J., Gao J., Sun F.-B. Wogonin induces beclin-1/pi3k and reactive oxygen species-mediated autophagy in human pancreatic cancer cells. Oncol. Lett. 2016;12:5059-5067.

    Not in our library10.3892/ol.2016.5367

  182. 182.

    Androutsopoulos V., Arroo R.R.J., Hall J.F., Surichan S., Potter G.A. Antiproliferative and cytostatic effects of the natural product eupatorin on mda-mb-468 human breast cancer cells due to cyp1-mediated metabolism. Breast Cancer Res. 2008;10:1-12.

    Not in our library10.1186/bcr2090

  183. 183.

    Lee K., Hyun Lee D., Jung Y.J., Shin S.Y., Lee Y.H. The natural flavone eupatorin induces cell cycle arrest at the g2/m phase and apoptosis in hela cells. Appl. Biol. Chem. 2016;59:193-199.

    Not in our library10.1007/s13765-016-0160-0

  184. 184.

    Sarvestani N.N., Sepehri H., Farimani M.M. Anticancer effect of eupatorin via bax/bcl-2 and mitochondrial membrane potential changes through ros mediated pathway in human colon cancer. Int. J. Pharmacogn. Phytochem. Res. 2015;7:1039-1046.

    Not in our library

  185. 185.

    Sarvestani N.N., Sepehri H., Delphi L., Farimani M.M. Eupatorin and salvigenin potentiate doxorubicin-induced apoptosis and cell cycle arrest in ht-29 and sw948 human colon cancer cells. Asian Pac. J. Cancer Prev. 2018;19:131-139.

    Not in our library10.22034/apjcp.2018.19.1.131

  186. 186.

    Estévez S., Marrero M.T., Quintana J., Estévez F. Eupatorin-induced cell death in human leukemia cells is dependent on caspases and activates the mitogen-activated protein kinase pathway. PLoS ONE. 2014;9:e112536.

    Not in our library10.1371/journal.pone.0112536

  187. 187.

    Fan Y., Lu H., Ma H., Feng F., Hu X., Zhang Q., Wang J., Xu Y., Zhao Q. Bioactive compounds of eriocaulon sieboldianum blocking proliferation and inducing apoptosis of hepg2 cells might be involved in aurora kinase inhibition. Food Funct. 2015;6:3746-3759.

    Not in our library10.1039/c5fo00371g

  188. 188.

    López De Las Hazas M.C., Mosele J.I., Macià A., Ludwig I.A., Motilva M.J. Exploring the colonic metabolism of grape and strawberry anthocyanins and their in vitro apoptotic effects in ht-29 colon cancer cells. J. Agric. Food Chem. 2017;65:6477-6487.

    Not in our library10.1021/acs.jafc.6b04096

  189. 189.

    Wang L.S., Stoner G.D. Anthocyanins and their role in cancer prevention. Cancer Lett. 2008;269:281-290.

    Not in our library10.1016/j.canlet.2008.05.020

  190. 190.

    Lin B.W., Gong C.C., Song H.F., Cui Y.Y. Effects of anthocyanins on the prevention and treatment of cancer. Br. J. Pharmacol. 2017;174:1226-1243.

    Not in our library10.1111/bph.13627

  191. 191.

    Rupasinghe H.P.V., Arumuggam N., Amararathna M., De Silva A.B.K.H. The potential health benefits of haskap (Lonicera caerulea L.): Role of cyanidin-3-o-glucoside. J. Funct. Foods. 2018;44:24-39.

    Not in our library10.1016/j.jff.2018.02.023

  192. 192.

    Sorrenti V., Vanella L., Acquaviva R., Cardile V., Giofrè S., Di Giacomo C. Cyanidin induces apoptosis and differentiation in prostate cancer cells. Int. J. Oncol. 2015;47:1303-1310.

    Not in our library10.3892/ijo.2015.3130

  193. 193.

    Hosseini M.M., Karimi A., Behroozaghdam M., Javidi M.A., Ghiasvand S., Bereimipour A., Aryan H., Nassiri F., Jangholi E. Cytotoxic and apoptogenic effects of cyanidin-3-glucoside on the glioblastoma cell line. World Neurosurg. 2017;108:94-100.

    Not in our library10.1016/j.wneu.2017.08.133

  194. 194.

    Tang J., Oroudjev E., Wilson L., Ayoub G. Delphinidin and cyanidin exhibit antiproliferative and apoptotic effects in mcf7 human breast cancer cells. Integr. Cancer Sci. Ther. 2015;2:82-86.

    Not in our library

  195. 195.
    Cyanidin Curtails Renal Cell Carcinoma Tumorigenesis · 2018
    Not checked
  196. 196.

    Hyun J.W., Chung H.S. Cyanidin and malvidin from oryza sativa cv. Heugjinjubyeo mediate cytotoxicity against human monocytic leukemia cells by arrest of g(2)/m phase and induction of apoptosis. J. Agric. Food Chem. 2004;52:2213-2217.

    Not in our library10.1021/jf030370h

  197. 197.

    Zhou L., Wang H., Yi J., Yang B., Li M., He D., Yang W., Zhang Y., Ni H. Anti-tumor properties of anthocyanins from lonicera caerulea ‘beilei’ fruit on human hepatocellular carcinoma: In vitro and in vivo study. Biomed. Pharmacother. 2018;104:520-529.

    Not in our library10.1016/j.biopha.2018.05.057

  198. 198.

    Karthi N., Kalaiyarasu T., Kandakumar S., Mariyappan P., Manju V. Pelargonidin induces apoptosis and cell cycle arrest: Via a mitochondria mediated intrinsic apoptotic pathway in ht29 cells. RSC Adv. 2016;6:45064-45076.

    Not in our library10.1039/c5ra20984f

  199. 199.

    Wang L.S., Sun X.D., Cao Y., Wang L., Li F.J., Wang Y.F. Antioxidant and pro-oxidant properties of acylated pelargonidin derivatives extracted from red radish (raphanus sativus var. Niger, brassicaceae). Food Chem. Toxicol. 2010;48:2712-2718.

    Not in our library10.1016/j.fct.2010.06.045

  200. 200.

    Chen Y., Wang S., Geng B., Yi Z. Pelargonidin induces antitumor effects in human osteosar—Coma cells via autophagy induction, loss of mitochondrial membrane potential, g2/m cell cycle arrest and downregula—tion of pi3k/akt signalling pathway. J. BUON. 2018;23:735-740.

    Not in our library

  201. 201.

    Ko H., Jeong M.-H., Jeon H., Sung G.-J., So Y., Kim I., Son J., Lee S.-W., Yoon H.-G., Choi K.-C. Delphinidin sensitizes prostate cancer cells to trail-induced apoptosis, by inducing dr5 and causing caspase-mediated hdac3 cleavage. Oncotarget. 2015;6:9970-9984.

    Not in our library10.18632/oncotarget.3667

  202. 202.

    Lim W., Song G. Inhibitory effects of delphinidin on the proliferation of ovarian cancer cells via pi3k/akt and erk 1/2 mapk signal transduction. Oncol. Lett. 2017;14:810-818.

    Not in our library10.3892/ol.2017.6232

  203. 203.

    Pal H.C., Sharma S., Strickland L.R., Agarwal J., Athar M., Elmets C.A., Afaq F. Delphinidin reduces cell proliferation and induces apoptosis of non-small-cell lung cancer cells by targeting egfr/vegfr2 signaling pathways. PLoS ONE. 2013;8:e77270.

    Not in our library10.1371/journal.pone.0077270

  204. 204.

    Alhosin M., León-González A.J., Dandache I., Lelay A., Rashid S.K., Kevers C., Pincemail J., Fornecker L.M., Mauvieux L., Herbrecht R., et al. Bilberry extract (antho 50) selectively induces redox-sensitive caspase 3-related apoptosis in chronic lymphocytic leukemia cells by targeting the bcl-2/bad pathway. Sci. Rep. 2015;5:1-10.

    Not in our library10.1038/srep08996

  205. 205.

    Bin Hafeez B., Asim M., Siddiqui I.A., Adhami V.M., Murtaza I., Mukhtar H. Delphinidin, a dietary anthocyanidin in pigmented fruits and vegetables: A new weapon to blunt prostate cancer growth. Cell Cycle. 2008;7:3320-3326.

    Not in our library10.4161/cc.7.21.6969

  206. 206.

    Hafeez B.B., Siddiqui I.A., Asim M., Malik A., Afaq F., Adhami V.M., Saleem M., Din M., Mukhtar H. A dietary anthocyanidin delphinidin induces apoptosis of human prostate cancer pc3 cells in vitro and in vivo: Involvement of nuclear factor-kappab signaling. Cancer Res. 2008;68:8564-8572.

    Not in our library10.1158/0008-5472.can-08-2232

  207. 207.

    Li H.Q., Luo Y., Qiao C.H. The mechanisms of anticancer agents by genistein and synthetic derivatives of isoflavone. Mini-Rev. Med. Chem. 2012;12:350-362.

    Not in our library10.2174/138955712799829258

  208. 208.

    Spagnuolu C., Russo G.L., Orhan l.E., Habtemariam S., Daglia M., Sureda A., Nabavi S.F., Devi K.P., Loizzo M.R., Tundis R., et al. Genistein and cancer: Current status, challenges, and future directions. Adv. Nutr. Int. Rev. J. 2015;6:408-419.

    Not in our library10.3945/an.114.008052

  209. 209.

    Choi E.J., Jung J.Y., Kim G.-H. Genistein inhibits the proliferation and differentiation of mcf-7 and 3t3-l1 cells via the regulation of erα expression and induction of apoptosis. Exp. Ther. Med. 2014;8:454-458.

    Not in our library10.3892/etm.2014.1771

  210. 210.

    Pan H., Zhou W., He W., Liu X., Ding Q., Ling L., Zha X., Wang S. Genistein inhibits mda-mb-231 triple-negative breast cancer cell growth by inhibiting nf-κb activity via the notch-1 pathway. Int. J. Mol. Med. 2012;30:337-343.

    Not in our library10.3892/ijmm.2012.990

  211. 211.

    Ullah M.F., Ahmad A., Zubair H., Khan H.Y., Wang Z., Sarkar F.H., Hadi S.M. Soy isoflavone genistein induces cell death in breast cancer cells through mobilization of endogenous copper ions and generation of reactive oxygen species. Mol. Nutr. Food Res. 2011;55:553-559.

    Not in our library10.1002/mnfr.201000329

  212. 212.

    Solomon L.A., Ali S., Banerjee S., Munkarah A.R., Morris R.T., Sarkar F.H. Sensitization of ovarian cancer cells to cisplatin by genistein: the role of NF-kappaB. J. Ovarian Res. 2008;1:9.

    Not in our library10.1186/1757-2215-1-9

  213. 213.

    Szliszka E., Krol W. Soy isoflavones augment the effect of trail-mediated apoptotic death in prostate cancer cells. Oncol. Rep. 2011;26:533-541.

    Not in our library10.3892/or.2011.1332

  214. 214.

    Dong X., Xu W., Sikes R.A., Wu C. Combination of low dose of genistein and daidzein has synergistic preventive effects on isogenic human prostate cancer cells when compared with individual soy isoflavone. Food Chem. 2013;141:1923-1933.

    Not in our library10.1016/j.foodchem.2013.04.109

  215. 215.

    Kumi-Diaka J., Merchant K., Haces A., Hormann V., Johnson M. Genistein-selenium combination induces growth arrest in prostate cancer cells. J. Med. Food. 2010;13:842-850.

    Not in our library10.1089/jmf.2009.0199

  216. 216.

    Qi W., Weber C.R., Wasland K., Savkovic S.D. Genistein inhibits proliferation of colon cancer cells by attenuating a negative effect of epidermal growth factor on tumor suppressor foxo3 activity. BMC Cancer. 2011;11:219.

    Not in our library10.1186/1471-2407-11-219

  217. 217.

    Qin J., Teng J., Zhu Z., Chen J., Huang W.J. Genistein induces activation of the mitochondrial apoptosis pathway by inhibiting phosphorylation of akt in colorectal cancer cells. Pharm. Biol. 2016;54:74-79.

    Not in our library10.3109/13880209.2015.1014921

  218. 218.

    Shafiee G., Saidijam M., Tavilani H., Ghasemkhani N., Khodadadi I. Genistein induces apoptosis and inhibits proliferation of ht29 colon cancer cells. Int. J. Mol. Cell. Med. 2016;5:178-191.

    Not in our library

  219. 219.

    Jin S., Zhang Q.Y., Kang X.M., Wang J.X., Zhao W.H. Daidzein induces mcf-7 breast cancer cell apoptosis via the mitochondrial pathway. Ann. Oncol. 2010;21:263-268.

    Not in our library10.1093/annonc/mdp499

  220. 220.

    Liu X., Suzuki N., Laxmi Y.R.S., Okamoto Y., Shibutani S. Anti-breast cancer potential of daidzein in rodents. Life Sci. 2012;91:415-419.

    Not in our library10.1016/j.lfs.2012.08.022

  221. 221.

    Park H.J., Jeon Y.K., You D.H., Nam M.J. Daidzein causes cytochrome c-mediated apoptosis via the bcl-2 family in human hepatic cancer cells. Food Chem. Toxicol. 2013;60:542-549.

    Not in our library10.1016/j.fct.2013.08.022

  222. 222.

    Sak K. Cytotoxicity of dietary flavonoids on different human cancer types. Pharmacogn. Rev. 2014;8:122-146.

    Not in our library10.4103/0973-7847.134247

  223. 223.

    Siddiqui I.A., Asim M., Hafeez B.B., Adhami V.M., Tarapore R.S., Mukhtar H. Green tea polyphenol egcg blunts androgen receptor function in prostate cancer. FASEB J. 2011;25:1198-1207.

    Not in our library10.1096/fj.10-167924

  224. 224.

    Albrecht D.S., Clubbs E.A., Ferruzzi M., Bomser J.A. Epigallocatechin-3-gallate (egcg) inhibits pc-3 prostate cancer cell proliferation via mek-independent erk1/2 activation. Chem.-Biol. Interact. 2008;171:89-95.

    Not in our library10.1016/j.cbi.2007.09.001

  225. 225.

    Sadava D., Whitlock E., Kane S.E. The green tea polyphenol, epigallocatechin-3-gallate inhibits telomerase and induces apoptosis in drug-resistant lung cancer cells. Biochem. Biophys. Res. Commun. 2007;360:233-237.

    Not in our library10.1016/j.bbrc.2007.06.030

  226. 226.

    Rieger-Christ K.M., Hanley R., Lodowsky C., Bernier T., Vemulapalli P., Roth M., Kim J., Yee A.S., Le S.M., Marie P.J., et al. The green tea compound, (−)-epigallocatechin-3-gallate downregulates n-cadherin and suppresses migration of bladder carcinoma cells. J. Cell. Biochem. 2007;102:377-388.

    Not in our library10.1002/jcb.21299

  227. 227.

    Righeschi C., Eichhorn T., Karioti A., Bilia A.R., Efferth T. Microarray-based mrna expression profiling of leukemia cells treated with the flavonoid, casticin. Cancer Genom. Proteomics. 2012;9:143-151.

    Not in our library

  228. 228.

    Liu F., Cao X., Liu Z., Guo H., Ren K., Quan M., Zhou Y., Xiang H., Cao J. Casticin suppresses self-renewal and invasion of lung cancer stem-like cells from a549 cells through down-regulation of pakt. Acta Biochim. Biophys. Sin. 2014;46:15-21.

    Not in our library10.1093/abbs/gmt123

  229. 229.

    Shen J.-K., Du H.-P., Yang M., Wang Y.-G., Jin J. Casticin induces leukemic cell death through apoptosis and mitotic catastrophe. Ann.Hematol. 2009;88:743-752.

    Not in our library10.1007/s00277-008-0677-3

  230. 230.

    Roh J.S., Han J.Y., Kim J.H., Hwang J.K. Inhibitory effects of active compounds isolated from safflower (Carthamus tinctorius L.) seeds for melanogenesis. Biol. Pharm. Bull. 2004;27:1976-1978.

    Not in our library10.1248/bpb.27.1976

  231. 231.

    Wirger A., Perabo F.G.E., Burgemeister S., Haase L., Schmidt D.H., Doehn C., Mueller S.C., Jocham D. Flavopiridol, an inhibitor of cyclin-dependent kinases, induces growth inhibition and apoptosis in bladder cancer cells in vitro and in vivo. Anticancer Res. 2005;25:4341-4347.

    Not in our library

  232. 232.

    Mayer F., Mueller S., Malenke E., Kuczyk M., Hartmann J.T., Bokemeyer C. Induction of apoptosis by flavopiridol unrelated to cell cycle arrest in germ cell tumour derived cell lines. Investig. New Drugs. 2005;23:205-211.

    Not in our library10.1007/s10637-005-6728-x

  233. 233.

    Schrump D.S., Matthews W., Chen G.A., Mixon A., Altorki N.K. Flavopiridol mediates cell cycle arrest and apoptosis in esophageal cancer cells. Clin Cancer Res. 1998;4:2885-2890.

    Not in our library

  234. 234.

    Patel V., Senderowicz A.M., Pinto D., Igishi T., Raffeld M., Quintanilla-Martinez L., Ensley J.F., Sausville E.A., Gutkind J.S. Flavopiridol, a novel cyclin-dependent kinase inhibitor, suppresses the growth of head and neck squamous cell carcinomas by inducing apoptosis. J. Clin. Investig. 1998;102:1674-1681.

    Not in our library10.1172/jci3661

  235. 235.

    Parker B.W., Kaur G., Nieves-Neira W., Taimi M., Kohlhagen G., Shimizu T., Losiewicz M.D., Pommier Y., Sausville E.A., Senderowicz A.M. Early induction of apoptosis in hematopoietic cell lines after exposure to flavopiridol. Blood. 1998;91:458-465.

    Not in our library

  236. 236.

    Dolečková I., Rárová L., Grúz J., Vondrusová M., Strnad M., Kryštof V. Antiproliferative and antiangiogenic effects of flavone eupatorin, an active constituent of chloroform extract of orthosiphon stamineus leaves. Fitoterapia. 2012;83:1000-1007.

    Not in our library10.1016/j.fitote.2012.06.002

  237. 237.

    Yoshino Y., Yuan B., Okusumi S., Aoyama R., Murota R., Kikuchi H., Takagi N., Toyoda H. Enhanced cytotoxic effects of arsenite in combination with anthocyanidin compound, delphinidin, against a human leukemia cell line, hl-60. Chem.-Biol. Interact. 2018;294:9-17.

    Not in our library10.1016/j.cbi.2018.08.008

  238. 238.

    Kamenickova A., Anzenbacherova E., Pavek P., Soshilov A.A., Denison M.S., Anzenbacher P., Dvorak Z. Pelargonidin activates the ahr and induces cyp1a1 in primary human hepatocytes and human cancer cell lines hepg2 and ls174t. Toxico. Lett. 2013;218:253-259.

    Not in our library10.1016/j.toxlet.2013.01.020

  239. 239.

    Sanaei M., Kavoosi F., Valiani A., Ghobadifar M.A. Effect of genistein on apoptosis and proliferation of hepatocellular carcinoma hepa1-6 cell line. Int. J. Prev. Med. 2018;9:12.

    Not in our library10.4103/ijpvm.ijpvm_249_16

  240. 240.

    Bi Y.L., Min M., Shen W., Liu Y. Genistein induced anticancer effects on pancreatic cancer cell lines involves mitochondrial apoptosis, g0/g1cell cycle arrest and regulation of stat3 signalling pathway. Phytomed. Int. J. Phytother. Phytopharmacol. 2018;39:10-16.

    Not in our library10.1016/j.phymed.2017.12.001

  241. 241.

    Gundogdu G., Dodurga Y., Cetin M., Secme M., Cicek B. The cytotoxic and genotoxic effects of daidzein on mia paca-2 human pancreatic carcinoma cells and ht-29 human colon cancer cells. Drug chem. Toxicol. 2018.

    Not in our library10.1080/01480545.2018.1527849

  242. 242.

    Hua F., Li C.H., Chen X.G., Liu X.P. Daidzein exerts anticancer activity towards skov3 human ovarian cancer cells by inducing apoptosis and cell cycle arrest, and inhibiting the raf/mek/erk cascade. Int. J. Mol. Med. 2018;41:3485-3492.

    Not in our library10.3892/ijmm.2018.3531

  243. 243.

    Han B.-J., Li W., Jiang G.-B., Lai S.-H., Zhang C., Zeng C.-C., Liu Y.-J. Effects of daidzein in regards to cytotoxicity in vitro, apoptosis, reactive oxygen species level, cell cycle arrest and the expression of caspase and bcl-2 family proteins. Oncol. Rep. 2015;34:1115-1120.

    Not in our library10.3892/or.2015.4133

  244. 244.

    Hollman P.C.H. Absorption, bioavailability, and metabolism of flavonoids. Pharm. Biol. 2004;42:74-83.

    Not in our library10.3109/13880200490893492

  245. 245.

    Manach C., Scalbert A., Morand C., Remesy C., Jimenez L. Polyphenols: Food sources and bioavailability. Am. J. Clin. Nutr. 2004;79:727-747.

    Not in our library10.1093/ajcn/79.5.727

  246. 246.

    Viskupičová J., Ondrejovič M., Šturdík E. Bioavailability and metabolism of flavonoids. J. Food Nutr. Res. 2008;47:151-162.

    Not in our library

  247. 247.
    The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids · 2017
    No notice
  248. 248.

    Scalbert A., Williamson G. Dietary intake and bioavailability of polyphenols. J. Nutr. 2000;130:2073S-2085S.

    Not in our library10.1093/jn/130.8.2073s

  249. 249.

    Hu M., Wu B., Liu Z. Bioavailability of polyphenols and flavonoids in the era of precision medicine. Mol. Pharm. 2017;14:2861-2863.

    Not in our library10.1021/acs.molpharmaceut.7b00545

  250. 250.
    Flavonoid Bioavailability and Attempts for Bioavailability Enhancement · 2013
    No notice
  251. 251.

    Barnes S. Soy isoflavones--phytoestrogens and what else? J. Nutr. 2004;134:1225S-1228S.

    Not in our library10.1093/jn/134.5.1225s

  252. 252.

    Messina M.J., Loprinzi C.L. Soy for breast cancer survivors: A critical review of the literature. J. Nutr. 2001;131:3095S-3108S.

    Not in our library10.1093/jn/131.11.3095s

  253. 253.

    Wang S., Zhang J., Chen M., Wang Y. Delivering flavonoids into solid tumors using nanotechnologies. Expert Opin. Drug Deliv. 2013;10:1411-1428.

    Not in our library10.1517/17425247.2013.807795

  254. 254.

    Goniotaki M., Hatziantoniou S., Dimas K., Wagner M., Demetzos C. Encapsulation of naturally occurring flavonoids into liposomes: Physicochemical properties and biological activity against human cancer cell lines. J. Pharm. Pharmacol. 2004;56:1217-1224.

    Not in our library10.1211/0022357044382

  255. 255.

    Guo D., Wu C., Li J., Guo A., Li Q., Jiang H., Chen B., Wang X. Synergistic effect of functionalized nickel nanoparticles and quercetin on inhibition of the smmc-7721 cells proliferation. Nanoscale Res. Lett. 2009;4:1395-1402.

    Not in our library10.1007/s11671-009-9411-x

  256. 256.

    Wong M.Y., Chiu G.N. Liposome formulation of co-encapsulated vincristine and quercetin enhanced antitumor activity in a trastuzumab-insensitive breast tumor xenograft model. Nanomedicine. 2011;7:834-840.

    Not in our library10.1016/j.nano.2011.02.001

  257. 257.

    Han Q., Yang R., Li J., Liang W., Zhang Y., Dong M., Besenbacher F., Wang C. Enhancement of biological activities of nanostructured hydrophobic drug species. Nanoscale. 2012;4:2078-2082.

    Not in our library10.1039/c2nr12013e

  258. 258.

    Yuan Z.P., Chen L.J., Wei Y.Q., Fan L.Y., Tang M.H., Yang G.L. Nanoliposomal quercetin inhibits formation of malignant ascites of hepatocellular carcinoma. Ai Zheng. 2006;25:941-945.

    Not in our library

  259. 259.

    Yuan Z.P., Chen L.J., Fan L.Y., Tang M.H., Yang G.L., Yang H.S., Du X.B., Wang G.Q., Yao W.X., Zhao Q.M., et al. Liposomal quercetin efficiently suppresses growth of solid tumors in murine models. Clin. Cancer Res. 2006;12:3193-3199.

    Not in our library10.1158/1078-0432.ccr-05-2365

  260. 260.

    Ferrer P., Asensi M., Segarra R., Ortega A., Benlloch M., Obrador E., Varea M.T., Asensio G., Jorda L., Estrela J.M. Association between pterostilbene and quercetin inhibits metastatic activity of b16 melanoma. Neoplasia. 2005;7:37-47.

    Not in our library10.1593/neo.04337

  261. 261.

    Harper C.E., Cook L.M., Patel B.B., Wang J., Eltoum I.A., Arabshahi A., Shirai T., Lamartiniere C.A. Genistein and resveratrol, alone and in combination, suppress prostate cancer in sv-40 tag rats. Prostate. 2009;69:1668-1682.

    Not in our library10.1002/pros.21017

  262. 262.

    Sakamoto K. Synergistic effects of thearubigin and genistein on human prostate tumor cell (pc-3) growth via cell cycle arrest. Cancer Lett. 2000;151:103-109.

    Not in our library10.1016/s0304-3835(99)00423-1

  263. 263.

    Wang P., Heber D., Henning S.M. Quercetin increased bioavailability and decreased methylation of green tea polyphenols in vitro and in vivo. Food Funct. 2012;3:635-642.

    Not in our library10.1039/c2fo10254d

  264. 264.

    Wang P., Vadgama J.V., Said J.W., Magyar C.E., Doan N., Heber D., Henning S.M. Enhanced inhibition of prostate cancer xenograft tumor growth by combining quercetin and green tea. J. Nutr. Biochem. 2014;25:73-80.

    Not in our library10.1016/j.jnutbio.2013.09.005

  265. 265.

    Amin A.R., Wang D., Zhang H., Peng S., Shin H.J., Brandes J.C., Tighiouart M., Khuri F.R., Chen Z.G., Shin D.M. Enhanced anti-tumor activity by the combination of the natural compounds (-)-epigallocatechin-3-gallate and luteolin: Potential role of p53. J. Biol. Chem. 2010;285:34557-34565.

    Not in our library10.1074/jbc.m110.141135

  266. 266.

    Somers-Edgar T.J., Scandlyn M.J., Stuart E.C., Le Nedelec M.J., Valentine S.P., Rosengren R.J. The combination of epigallocatechin gallate and curcumin suppresses er alpha-breast cancer cell growth in vitro and in vivo. Int. J. Cancer. 2008;122:1966-1971.

    Not in our library10.1002/ijc.23328

  267. 267.

    Mertens-Talcott S.U., Bomser J.A., Romero C., Talcott S.T., Percival S.S. Ellagic acid potentiates the effect of quercetin on p21waf1/cip1, p53, and map-kinases without affecting intracellular generation of reactive oxygen species in vitro. J. Nutr. 2005;135:609-614.

    Not in our library10.1093/jn/135.3.609

  268. 268.

    Mertens-Talcott S.U., Percival S.S. Ellagic acid and quercetin interact synergistically with resveratrol in the induction of apoptosis and cause transient cell cycle arrest in human leukemia cells. Cancer Lett. 2005;218:141-151.

    Not in our library10.1016/j.canlet.2004.06.007

  269. 269.

    Mertens-Talcott S.U., Talcott S.T., Percival S.S. Low concentrations of quercetin and ellagic acid synergistically influence proliferation, cytotoxicity and apoptosis in molt-4 human leukemia cells. J. Nutr. 2003;133:2669-2674.

    Not in our library10.1093/jn/133.8.2669

  270. 270.

    Suganuma M., Okabe S., Kai Y., Sueoka N., Sueoka E., Fujiki H. Synergistic effects of (—)-epigallocatechin gallate with (—)-epicatechin, sulindac, or tamoxifen on cancer-preventive activity in the human lung cancer cell line pc-9. Cancer Res. 1999;59:44-47.

    Not in our library

  271. 271.

    Suganuma M., Kurusu M., Suzuki K., Tasaki E., Fujiki H. Green tea polyphenol stimulates cancer preventive effects of celecoxib in human lung cancer cells by upregulation of gadd153 gene. Int. J. Cancer. 2006;119:33-40.

    Not in our library10.1002/ijc.21809

  272. 272.

    Adhami V.M., Malik A., Zaman N., Sarfaraz S., Siddiqui I.A., Syed D.N., Afaq F., Pasha F.S., Saleem M., Mukhtar H. Combined inhibitory effects of green tea polyphenols and selective cyclooxygenase-2 inhibitors on the growth of human prostate cancer cells both in vitro and in vivo. Clin. Cancer Res. 2007;13:1611-1619.

    Not in our library10.1158/1078-0432.ccr-06-2269

  273. 273.

    Stearns M.E., Wang M. Synergistic effects of the green tea extract epigallocatechin-3-gallate and taxane in eradication of malignant human prostate tumors. Transl. Oncol. 2011;4:147-156.

    Not in our library10.1593/tlo.10286

  274. 274.

    Stearns M.E., Amatangelo M.D., Varma D., Sell C., Goodyear S.M. Combination therapy with epigallocatechin-3-gallate and doxorubicin in human prostate tumor modeling studies: Inhibition of metastatic tumor growth in severe combined immunodeficiency mice. Am. J. Pathol. 2010;177:3169-3179.

    Not in our library10.2353/ajpath.2010.100330

  275. 275.

    Liang G., Tang A., Lin X., Li L., Zhang S., Huang Z., Tang H., Li Q.Q. Green tea catechins augment the antitumor activity of doxorubicin in an in vivo mouse model for chemoresistant liver cancer. Int. J. Oncol. 2010;37:111-123.

    Not in our library

  276. 276.

    Luo T., Wang J., Yin Y., Hua H., Jing J., Sun X., Li M., Zhang Y., Jiang Y. (−)-epigallocatechin gallate sensitizes breast cancer cells to paclitaxel in a murine model of breast carcinoma. Breast Cancer Res. 2010;12:R8.

    Not in our library10.1186/bcr2473

  277. 277.

    Chan M.M., Soprano K.J., Weinstein K., Fong D. Epigallocatechin-3-gallate delivers hydrogen peroxide to induce death of ovarian cancer cells and enhances their cisplatin susceptibility. J. Cell Physiol. 2006;207:389-396.

    Not in our library10.1002/jcp.20569

  278. 278.

    Tang S.N., Fu J., Shankar S., Srivastava R.K. Egcg enhances the therapeutic potential of gemcitabine and cp690550 by inhibiting stat3 signaling pathway in human pancreatic cancer. PLoS ONE. 2012;7:e31067.

    Not in our library10.1371/journal.pone.0031067

  279. 279.

    Staedler D., Idrizi E., Kenzaoui B.H., Juillerat-Jeanneret L. Drug combinations with quercetin: Doxorubicin plus quercetin in human breast cancer cells. Cancer Chemother. Pharmacol. 2011;68:1161-1172.

    Not in our library10.1007/s00280-011-1596-x

  280. 280.

    Sharma H., Sen S., Singh N. Molecular pathways in the chemosensitization of cisplatin by quercetin in human head and neck cancer. Cancer Biol. Ther. 2005;4:949-955.

    Not in our library10.4161/cbt.4.9.1908

  281. 281.

    Banerjee S., Zhang Y., Ali S., Bhuiyan M., Wang Z., Chiao P.J., Philip P.A., Abbruzzese J., Sarkar F.H. Molecular evidence for increased antitumor activity of gemcitabine by genistein in vitro and in vivo using an orthotopic model of pancreatic cancer. Cancer Res. 2005;65:9064-9072.

    Not in our library10.1158/0008-5472.can-05-1330

  282. 282.

    Mohammad R.M., Banerjee S., Li Y., Aboukameel A., Kucuk O., Sarkar F.H. Cisplatin-induced antitumor activity is potentiated by the soy isoflavone genistein in bxpc-3 pancreatic tumor xenografts. Cancer. 2006;106:1260-1268.

    Not in our library10.1002/cncr.21731

  283. 283.

    Banerjee S., Zhang Y., Wang Z., Che M., Chiao P.J., Abbruzzese J.L., Sarkar F.H. In vitro and in vivo molecular evidence of genistein action in augmenting the efficacy of cisplatin in pancreatic cancer. Int. J. Cancer. 2007;120:906-917.

    Not in our library10.1002/ijc.22332

  284. 284.

    Raffoul J.J., Sarkar F.H., Hillman G.G. Radiosensitization of prostate cancer by soy isoflavones. Curr. Cancer Drug Targets. 2007;7:759-765.

    Not in our library10.2174/156800907783220408

  285. 285.

    Raffoul J.J., Banerjee S., Singh-Gupta V., Knoll Z.E., Fite A., Zhang H., Abrams J., Sarkar F.H., Hillman G.G. Down-regulation of apurinic/apyrimidinic endonuclease 1/redox factor-1 expression by soy isoflavones enhances prostate cancer radiotherapy in vitro and in vivo. Cancer Res. 2007;67:2141-2149.

    Not in our library10.1158/0008-5472.can-06-2147

  286. 286.

    Raffoul J.J., Banerjee S., Che M., Knoll Z.E., Doerge D.R., Abrams J., Kucuk O., Sarkar F.H., Hillman G.G. Soy isoflavones enhance radiotherapy in a metastatic prostate cancer model. Int. J. Cancer. 2007;120:2491-2498.

    Not in our library10.1002/ijc.22548

  287. 287.

    Gupta S.C., Patchva S., Aggarwal B.B. Therapeutic roles of curcumin: Lessons learned from clinical trials. AAPS J. 2013;15:195-218.

    Not in our library10.1208/s12248-012-9432-8

  288. 288.

    Kanwar J., Taskeen M., Mohammad I., Huo C., Chan T.H., Dou Q.P. Recent advances on tea polyphenols. Front. Biosci. 2012;4:111-131.

    Not in our library10.2741/e363

  289. 289.

    Saldanha S.N., Tollefsbol T.O. The role of nutraceuticals in chemoprevention and chemotherapy and their clinical outcomes. J. Oncol. 2012;2012:192464.

    Not in our library10.1155/2012/192464

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    Paller C.J., Rudek M.A., Zhou X.C., Wagner W.D., Hudson T.S., Anders N., Hammers H.J., Dowling D., King S., Antonarakis E.S., et al. A phase i study of muscadine grape skin extract in men with biochemically recurrent prostate cancer: Safety, tolerability, and dose determination. Prostate. 2015;75:1518-1525.

    Not in our library10.1002/pros.23024

  291. 291.

    Zhang G., Wang Y., Zhang Y., Wan X., Li J., Liu K., Wang F., Liu K., Liu Q., Yang C., et al. Anti-cancer activities of tea epigallocatechin-3-gallate in breast cancer patients under radiotherapy. Curr. Mol. Med. 2012;12:163-176.

    Not in our library10.2174/156652412798889063

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