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Anti-cancer natural products isolated from chinese medicinal herbs

Wen Tan, Jinjian Lu, Mingqing Huang and 10 more

Chinese Medicine · 2011 · Review

Abstract

In recent years, a number of natural products isolated from Chinese herbs have been found to inhibit proliferation, induce apoptosis, suppress angiogenesis, retard metastasis and enhance chemotherapy, exhibiting anti-cancer potential both in vitro and in vivo . This article summarizes recent advances in in vitro and in vivo research on the anti-cancer effects and related mechanisms of some promising natural products. These natural products are also reviewed for their therapeutic potentials, including flavonoids (gambogic acid, curcumin, wogonin and silibinin), alkaloids (berberine), terpenes (artemisinin, β-elemene, oridonin, triptolide, and ursolic acid), quinones (shikonin and emodin) and saponins (ginsenoside Rg 3 ), which are isolated from Chinese medicinal herbs. In particular, the discovery of the new use of artemisinin derivatives as excellent anti-cancer drugs is also reviewed.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 18, 2026. Paragraph numbers are ours, so an answer can point at one.

Background

1Surgery, chemotherapy and radiotherapy are the main conventional cancer treatment often supplemented by other complementary and alternative therapies in China. While chemotherapy is one of the most extensively studied methods in anti-cancer therapies, its efficacy and safety remain a primary concern as toxicity and other side effects of chemotherapy are severe. Moreover, multi-drug resistant cancer is even a bigger challenge. Medicinal herbs are main sources of new drugs. Newman et al. reported that more than half of the new chemicals approved between 1982 and 2002 were derived directly or indirectly from natural products. Some active compounds have been isolated from Chinese medicinal herbs and tested for anti-cancer effects. For example, β-elemene, a compound isolated from Curcuma wenyujin Y. H. Chen et C. Ling (Wenyujin), is used as an anti-cancer drug in China. For this study, we searched three databases, namely PubMed, Scopus and Web of Science, using keywords "cancer", "tumor", "neoplastic" and "Chinese herbs" or "Chinese medicine". Publications including research and review papers covered in this review were dated between 1987 and 2011, the majority of which were published between 2007 and 2011. Chinese herb-derived ingredients, including flavonoids, alkaloids, terpenes, quinones and saponins, were found.

Gambogic acid (GA)

2GA (Figure 1A) is the principal active ingredient of gamboges which is the resin from various Garcinia species including Garcinia hanburyi Hook.f. (Tenghuang). GA has various biological effects, such as anti-inflammatory, analgesic and anti-pyretic as well as anti-cancer activities. In vitro and in vivo studies have demonstrated its potential as an excellent cytotoxicity against a variety of malignant tumors, including glioblastoma, as well as cancers of the breast, lung and liver. GA is currently investigated in clinical trials in China.

3GA induces apoptosis in various cancer cell types and the action mechanisms of GA remain unclear. Transferrin receptor (TfR) significantly over-expressed in a variety of cancers cells may be the primary target of GA. The binding of GA to TfR in a manner independent of the transferrin binding site, leading to the rapid apoptosis of tumor cells. Proteomics analysis suggests that stathmin may be another molecular target of GA. The importance of the role of p53 in GA-induced apoptosis remains controversial. Furthermore, GA antagonizes the anti-apoptotic B-cell lymphoma 2 (Bcl-2) family of proteins and inhibits all six human Bcl-2 proteins to various extents, most potently inhibiting myeloid cell leukemia sequence 1 (Mcl-1) and Bcl-B, as evidenced by a half maximal inhibitory concentration (IC50) lower than 1 μM. Moreover, GA also influences other anti-cancer targets, such as nuclear factor-kappa B (NF-κB) and topoisomerase IIα.

4GA causes a dose-dependent suppression of cell invasion and inhibits lung metastases of MDA-MB-435 cells in vivo through protein kinase C (PKC)-mediated matrix metalloproteinase-2 (MMP-2) and matrix metallopeptidase-9 (MMP-9) inhibition. GA also exhibits significant anti-metastatic activities on B16-F10 melanoma cancer cells partially through the inhibition of the cell surface expression of integrin α4 in C57BL/6 mice.

5Notably, the combination of GA with other compounds enhances their anti-cancer activities. For example, He et al. reports that proliferative inhibition and apoptosis induction are much more visibly increased when Tca8113 cells are treated with combined GA and celastrol, indicating that the combination of GA and celastrol can be a promising modality for treating oral squamous cell carcinoma. Another study showed that GA in combined use with 5-fluorouracil (5-FU) induced considerably higher apoptosis rates in BGC-823 human gastric cells and inhibited tumor growth in human xenografts. Furthermore, low concentrations of GA were found to cause a dramatic increase in docetaxel-induced cytotoxicity in docetaxel-resistant BGC-823/Doc cells. Magnetic nanoparticles of Fe3O4 (MNPs-Fe3O4) were reported to enhance GA-induced cytotoxicity and apoptosis in K562 human leukemia cells.

Curcumin

6Curcumin (Figure 1B) is the main active flavonoid derived from the rhizome of Curcuma longa (Jianghuang), with its dry herb weight consisting of up to 3.08% curcumin. Curcumin has been used to treat cardiovascular disease, inflammation and arthritis. Epidemiological studies have found that incidence of several cancers is low in India where curcumin is widely consumed, suggesting that curcumin intake plays a role in cancer prevention. Other studies have also indicated that curcumin inhibits cell proliferation and survival in breast cancer, colon cancer, prostate cancer, gastric cancer, leukemia, lymphoma and melanoma. Curcumin induces cell apoptosis through complex intrinsic and extrinsic pathways. Curcumin binds to more than 30 different protein targets, including transcript factors (NF-κB and activator protein-1), growth factor receptors [epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2)], kinases [mitogen-activated protein kinase (MAPK), PKC and protein kinase A (PKA)], inflammatory cytokines [tumor necrosis factor (TNF) and interleukins], cell cycle-related proteins (p53 and p21), matrix metalloproteinases (MMPs) and urokinase plasminogen activators (u-PA). Daily oral administration of curcumin suppresses metastasis in breast, colon, lung and medulloblastoma cancers. The suppression involves the regulation of metastatic proteins, such as vascular endothelial growth factor (VEGF), MMP-2, MMP-9 and intercellular adhesion molecules.

7Curcumin induces non-apoptotic cell death, such as autophagic cell death, which involves the degradation of the cell's own components through lysosomal machinery. In vitro and in vivo studies have demonstrated that curcumin induces autophagic cell death, as evidenced by the immunoreactivity of microtubule-associated protein light chain 3 (LC3) in myeloid leukemia cells. The action mechanism is attributed to the inhibition of the Akt/mammalian target of rapamycin/p70 ribosomal protein S6 kinase pathway and activation of extracellular signal-regulated kinase 1/2 by curcumin in malignant glioma cells. In addition, autophagic inhibitor bafilomycin A1 suppresses curcumin-induced cell death. Another type of non-apoptotic cell death induced by curcumin is paraptosis which is observed in malignant breast cancer cells but not in normal breast cells. Curcumin induces paraptotic events (eg the promotion of vacuolation accompanied with mitochondrial and/or endoplasmic reticular swelling and fusion) and decreases the level of paraptotic inhibitor protein AIP-1/Alix. These paraptotic events are attributed to superoxide anion and proteasomal dysfunction.

8Curcumin reduces toxicity induced by anti-cancer agents, sensitizes chemo-resistant cancer cells and demonstrates synergic effects with different chemotherapeutic agents such as doxorubicin, 5-FU, paclitaxel, vincristine, melphalan, butyrate, cisplatin, celecoxib, vinorelbine, gemcitabine, oxaliplatin, etoposide, sulfinosine, thalidomide, suberoylanilide hydroxamic acid, dasatinib and bortezomib. Prior administration of curcumin reduces the DNA damage and oxidative stress induced by cyclophosphamide (CXC), improves uroprotective efficacy in the CXC hemorrhagic cystitis model and suppresses early lung damage in CXC-treated rats. Curcumin alleviates the side effects of mitomycin C, as evidenced by decreased lipid peroxidation and DNA damage. Furthermore, curcumin reduces weight loss and improves kidney function and bone marrow suppression in animal studies. When combined with oxaliplatin, curcumin decreases the proliferative capacity of oxaliplatin-resistant cell lines and enhances the cytotoxicity of oxaliplatin in an in vitro oxaliplatin-resistant model. Additionally, curcumin protects healthy cells against radiation and sensitizes tumor cells to radiation therapy.

9Clinical trials have been or are currently being conducted to evaluate the tolerance, safety, pharmacokinetics and efficiency of curcumin as well as its combination therapy with current anti-cancer drugs. A phase I clinical trial found no dose-limiting toxicity in patients treated with an oral-dose of up to 8g/day of curcumin. The recommendation is seven consecutive doses (6g/day) of curcumin every three weeks in combination with a standard dose of docetaxel. Improvements in biological and clinical responses were observed in most treated patients. A phase II trial of gemcitabine-resistant pancreatic cancer found chemotherapeutic drugs in combined use with curcumin to be sufficiently safe, feasible and efficient. While the bioavailability of curcumin is relatively poor, two out of 21 patients in the phase II trial showed clinical biological responses; one patient exhibited marked tumor regression coupled with a significant increase in serum cytokine levels.

Wogonin

10Wogonin (Figure 1C) is one of the flavonoids isolated from Scutellaria baicalensis Georgi (Huangqin), with its dry herb weight consisting of up to 0.39 mg/100 mg of wogonin. Wogonin has been widely used in the treatment of various inflammatory diseases owing to its inhibition of nitric oxide (NO), prostaglandin E2 and pro-inflammatory cytokines production, as well as its reduction of cyclooxygenase-2 (COX-2). In vitro studies have shown wogonin to possess cytostatic and cytotoxic activities against several human tumor cell lines.

11Wogonin induces apoptosis through the mediation of Ca2+ and/or inhibition of NF-κB, shifting O2- to H2O2 to some extent; H2O2, in turn, serves as a signaling molecule that activates phospholipase Cγ. Ca2+ efflux from the endoplasmic reticulum is then regulated, leading to the activation of Bcl-2-associated agonist of cell death. Wogonin may also directly activate the mitochondrial Ca2+ channel uniporter and enhance Ca2+ uptake, resulting in Ca2+ overload and mitochondrial damage. Furthermore, wogonin induces cell type-dependent cell cycle inhibitions in cancer cells, such as those observed in human cervical carcinoma HeLa cells at the G1 phase and in THP-1 cells at the G2/M phase respectively. Unlike the inhibitory effect of baicalein and baicalin on normal human fetal lung diploid TIG-1 cells, wogonin imposes minor or almost no toxicity on normal peripheral T cells, TIG-1 cells and human prostate epithelial cells. This selective inhibition of wogonin is due to a high expression of L-type voltage dependent Ca2+ channels in cancer cells. In addition, wogonin suppresses VEGF-stimulated migration and tube formation in HUVEC by inhibiting VEGF receptor 2 (VEGFR2) instead of VEGFR1 phosphorylation.

12The synergistic effect of wogonin on chemotherapy drugs, such as etoposide, has also been investigated. Wogonin significantly improves etoposide-induced apoptosis in cancer cells in a similar capacity as the typical P-glycoprotein (P-gp) inhibitors verapamil and cyclosporine A. However, other P-gp substrates, such as doxorubicin and vinblastine, do not show any synergistic effect. Similar effect was also found when combination treatment with 5-FU in human gastric MGC-803 cells and in MGC-803 transplanted nude mice. The underlying mechanisms might be due to its pro-apoptotic effect and inhibition of NF-κB nuclear translocation activity.

13Anti-inflammatory and anti-viral activities of wogonin may also contribute to tumor prevention. Wogonin is a good anti-cancer candidate due to its broad toxicities to various types of tumor cell lines and the low toxicities to normal tissues, as well as the synergistic effects.

Silibinin

14Silibinin (Figure 1D), a mixture of flavonoids derived from Silybum marianum (Shuifeiji), is therapeutically used for the treatment of hepatic diseases in China, Germany and Japan. Silibinin has effects on many cancers, such as prostate, colon, bladder and lung cancers, particularly the migration, invasion and metastasis of cancer cells. In a transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model, silibinin inhibits tumor growth, progression, local invasion and distant metastasis. Silibinin induces both death receptor-mediated and mitochondrial-mediated apoptosis in human breast cancer MCF-7 cells. Silibinin also reduces hepatocellular carcinoma xenograft growth through the inhibition of cell proliferation, cell cycle progression, as well as phosphatase and tensin homolog/P-Akt and extracellular signal-regulated kinase (ERK) signaling. These effects induce apoptosis and increase histone acetylation and superoxide dismutase-1 (SOD-1) expression on human hepatocellular carcinoma xenografts. Not only does silibinin inhibit primary prostatic tumor progress but also protects against angiogenesis and late-stage metastasis. Therefore, silibinin may have a potential for improving survival and reducing morbidity in prostate cancer patients.

15Silibinin exerts anti-cancer activity mainly by blocking cell cycle progression and induces G1 cell cycle arrest in a dose- and time-dependent manner in large cell carcinoma H1299 and H460 cells and bronchioalveolar carcinoma H322 cells. Silibinin modulates the protein levels of cyclin-dependent kinases (CDKs; 4, 6 and 2), cyclins (D1, D3 and E), and CDK inhibitors (p18/INK4C, p21/Waf1 and p27/Kip1) in a differential manner in the above-mentioned cell lines. Silibinin also regulates multiple cellular proliferative pathways in cancer cells, including receptor tyrosine kinases (RTKs), androgen receptors, signal transducers and activators of transcription (STATs), NF-κB. Moreover, silibinin inhibits the constitutive activation of STAT3 and causes caspase activation and apoptotic cell death in human prostate carcinoma DU145 cells.

16The combined use of silibinin with 1,25-dihydroxyvitamin D3 promotes the expression of both differentiation-promoting and -inhibiting genes in acute myelogenous leukemia cells and the latter can be neutralized by a highly specific pharmacological inhibitor, suggesting the therapeutic potential of silibinin.

Berberine

17Berberine (Figure 1E) is an isoquinoline alkaloid isolated from Coptidis Rhizoma (Huanglian), which is a Chinese medicinal herb for heat dissipation and detoxification, with its dry herb weight consisting of up to 7.1 mg/100 mg of berberine. Berberine has diverse pharmacological activities and is especially used as an antibacterial and anti-inflammatory gastrointestinal remedy in China. Berberine has anti-proliferative effects on cancer cells has been documented. Multiple targets of berberine have been identified, including mitochondria, DNA or RNA, DNA topoisomerases, estrogen receptors, MMPs, p53 and NF-κB. Berberine exerts cytotoxicity and inhibits telomerase and topoisomerase in cancer cells by specifically binding to oligonucleotides or polymorphic nucleic acid and by stabilizing DNA triplexes or G-quadruplexes; the electrostatic interactions may be quantified in terms of the Hill model of cooperative interactions.

18Cell cycle regulation is a common target mechanism in anti-cancer therapies. A low-dose (12.5-50 μM) berberine treatment induces G1 phase arrest whereas doses higher than 50 μM induce G2 phase arrest in mouse melanoma K1735-M2 and human melanoma WM793 cells. Moreover, 50 μM berberine decreases cyclin B1 levels and induces cycle arrest at the G1 phase in human lung cancer H1299 and A549 cell lines. Even in anoikis-resistant human breast cancer MDA-MB-231 and MCF-7 cells, 10 or 20 μM doses of berberine is superior to 5 or 10 nM of doxorubicine respectively by inducing cell cycle arrest at the G0/G1 phase.

19In human breast cancer MCF-7 cells, berberine induces apoptosis through a mitochondrial dependent pathway by increasing the Bcl-2-associated × protein (Bax)/Bcl-2 protein ratio, activating caspases and inducing poly (ADP-ribose) polymerase (PARP) cleavage. These apoptotic processes also occur in human tongue squamous carcinoma cancer-4 and human glioblastoma T98G cells. Accumulation of berberine on mitochondrial membranes alters the binding between adenine nucleotide translocator and bongkrekic acid, thereby inducing depolarization and fragmentation which may contribute to mitochondrial respiration inhibition and mitochondrial dysfunction. In the p53-expressing human neuroblastoma SK-N-SH and p53-deficient SK-N-MC cells, the role of p53 in berberine's anti-neoplastic function is highlighted by the cytotoxic effects and apoptotic gene expression accompanied by caspase-3 activation.

20In addition to apoptotic alteration induced by berberine, recent findings are about anti-cancer mechanisms that have a higher propensity to cause autophagy. Berberine induces autophagic cell death in human hepatocellular liver carcinoma cell lines (HepG2) and MHCC97-L cells, which may be diminished by cell death inhibitor 3-methyladenine through beclin-1 activation and mammalian target of rapamycin (mTOR) signaling pathway inhibition. In addition, berberine also modifies LC3, an autophagic marker, in human lung cancer A549 cells, indicating that autophagy may play a crucial role in berberine-induced cancer cell death.

21Berberine also inhibits tumor metastasis and invasion. For example, berberine inhibits 12-O-Tetradecanoylphorbol 13-acetate (TPA)-induced cell migration and blocks prostaglandin E (EP) receptor 4 agonist-induced migration by reducing EP receptors 2 and 4 in A375 and Hs294 cells. Even at low doses, berberine suppresses Rho GTPase activation and induces migration and motility inhibition in HONE1 cells. Berberine also inhibits Rho kinase-mediated Ezrin phosphorylation at Thr (567) in 5-8F cells, leading to a 51.1% inhibition of tumor metastasis to the lymph nodes in vivo. A combination of As2O3 (5 μM) and berberine (10 μM) inhibit the formation of a cell confluent layer by blocking PKCα and ξ, consistent with reduced levels of myelocytomatosis oncogene (Myc), Jun proto-oncogene, metallothionein 1-MMP and MMP-2.

22Berberine enhances chemo- and radio-sensitivity, implying its potential as an adjuvant in cancer therapy. Combined with chemotherapy drugs such as cisplatin or As2O3, berberine exhibits significant cytotoxicity in HeLa and SH-SY5Y cells compared with monotherapy. When combined with γ radiation, the apoptotic effect is significantly enhanced in HepG2 cells. Berberine also alleviates chemo-resistance by down-regulating overexpressed transformed mouse 3T3 cell double minute-2 and activating p53 in acute lymphoblastic leukemia cells. Berberine's poor bioavailability makes it less likely to be an independent anti-tumor agent. Berberine is nevertheless a potential natural compound for alternative cancer therapy.

Artemisinin and its derivatives (ARTs)

23Artemisinin (Figure 1F) is an active terpene of the Chinese medicinal herb Artemisia annua L. (Huanghuahao) used in China to treat malaria and fever. ARTs, such as dihydroartemisinin (DHA) and artesunate (Figure 1G), exhibit anti-cancer activities in vitro and in vivo. DHA is one of the main metabolites of ARTs and artesunate is a semi-synthesized derivative of ARTs; both compounds exhibit anti-cancer potentials.

24The anti-cancer potential of ARTs has been demonstrated in various cancer cells including those of leukemia and other cancer cells of breast, ovary, liver, lung, pancreas and colon. The selective anti-cancer potential of ARTs was related with the expression of different molecules such as c-MYC, cdc25A, EGFR, γ-glutamycysteine synthetase (GLCLR). ARTs also exert anti-cancer effects in vivo in multiple cancer types. For example, either DHA or artesunate has anti-cancer activity against pancreatic cancer xenografts.

25The anti-cancer mechanism of ARTs is likely to be related to the cleavage of the iron- or heme-mediated peroxide bridge, followed by the generation of reactive oxygen species (ROS). According to Efferth et al., CCRF-CEM and U373 cells are sensitive to a combined treatment of ARTs and iron (II)-glycine sulfate or holotransferring. Pretreatment with deferoxamine mesylate salt (an iron chelator) visibly reduces DHA-induced apoptosis in HL-60 leukemia cells. The anti-cancer potential of ARTs is possibly connected to the expression of TfR. The synergism of artesunate and iron (II)-glycine sulfate co-treatment is unsuitable for all types of tumor cells. Endoplasmic reticulum stress is partially involved in some cases of ARTs-mediated anti-proliferation.

26ARTs induce cell cycle arrest in various cell types. For example, DHA and artesunate effectively mediate G1 phase arrest in HepG2 and Hep3B cells. DHA reduces cell number in the S phase in HCT116 colon cancer cells. Interestingly, DHA also arrests the G2 phase in OVCA-420 ovarian cancer cells. Thus, ART-mediated cell cycle arrest is possibly cell type dependent. ARTs also induce apoptotic cell death in a number of cell types, in which the mitochondrial-mediated apoptotic pathway plays a decisive role. For instance, DHA enhances Bax and reduces Bcl-2 expression in cancer cells. DHA-induced apoptosis is abrogated by the loss of Bak and is largely reduced in cells with siRNA-mediated downregulation of Bak or NOXA. However, DHA activates caspase-8, which is related to the death receptor-mediated apoptotic pathway in HL-60 cells. DHA enhances Fas expression and activates caspase-8 in ovarian cancer cells. DHA also enhances death receptor 5 and activates both mitochondrial- and death receptor-mediated apoptotic pathways in prostate cancer cells. ARTs-induced apoptosis in cancer cells may involve p38 MAPK rather than p53.

27ARTs inhibit angiogenesis which is a vital process in metastasis. DHA inhibits chorioallantoic membrane angiogenesis at low concentrations and decreases the levels of two major VEGF receptors on HUVEC. Conditioned media from K562 cells pre-treated with DHA inhibits VEGF expression and secretion in chronic myeloid leukemia K562 cells, leading to angiogenetic activity decrease. Artemisinin inhibits cell migration and concomitantly decreases the expression of MMP2 and the αvβ3 integrins in human melanoma cells. ARTs also regulate the levels of u-PA, MMP2, MMP7 and MMP9 all of which are related to metastasis.

28ARTs exert synergistic effects with other compounds. Combination of DHA and caboplatin significantly reduces the development of ovarian cancer as compared with DHA only. Combined use of DHA or artesunate with gencitabine inhibits the growth of HepG2 and Hep3B transplanted tumors. Supra-additive inhibition of cell growth in some glioblastoma multiforme cells is observable when artesunate is in combined use with EGFR inhibitor OSI-774. DHA not only up-regulates death receptor 5 expression but also cooperates with TNF-related apoptosis-inducing ligand (TRAIL) to induce apoptosis in human prostate cancer cells. Therefore, either used alone or in combination with other compounds, ARTs are promising compounds for chemotherapy.

β-elemene

29Elemene (Figure 1H) is a sesquiterpene mixture isolated from more than 50 Chinese herbs and plants, such as Curcuma wenyujin Y. H. Chen et C. Ling (Wenyujin). Elemene is mainly composed of β- and δ- and γ-elemene, with β-elemene accounting for 60%-72% of all three isoforms. β-elemene exerts anti-cancer potential in brain, laryngeal, lung, breast, prostate, cervical, colon and ovarian carcinomas. Elemene shows synergistic effects in combination with other chemotherapeutic drugs, leading to the blockade of cell cycle progression by modulating the G2 cell cycle checkpoint and inducing G2/M arrest in human non-small cell lung cancer (NSCLC) and ovarian carcinoma cells while inducing G0/G1 phase arrest in glioblastoma cell lines through phosphorylation of p38 MAPK. In NSCLC cells, β-elemene induces cell arrest at the G2/M phase by increasing phospho-Cdc2 (Tyr15) and p27/Kip1, and by decreasing phospho-Cdc2 (Thr161) and cyclin B1. Moreover, elemene reduces the expression of Cdc25C, activates Cdc2 and increases Chk2. β-elemene combined with cisplatin also mediate G2/M cell cycle arrest in chemo-resistant ovarian carcinoma cells through down-regulation of cyclin B1 and Cdc2 by elevating the levels of phosphorylation of Cdc2, Cdc25C, p53, p21/Waf1, p27/Kip1 and GADD45. β-elemene also induces mitochondrial-mediated apoptosis in prostate cancer and NSCLC cells. Combining β-elemene with cisplatin, docetaxel and taxanes significantly increases its inhibitory effect in androgen-independent prostate carcinoma DU145 and PC-3 cells, as well as in NSCLC H460 and A549 cells. β-elemene enhances cellular uptake of taxanes due to the alteration of cell membrane permeability may partly account for its synergistic effects with taxanes. Elemene inhibits the growth of human epidermoid and thyroid cancer cells in vivo, and passes through the blood-brain barrier, suggesting its potential for treating cerebral malignancy.

30β-elemene has been approved by China's State Food and Drug Administration as a second class innovative drug and is prescribed as an adjuvant drug for some tumor therapies in China.

Oridonin

31Oridonin (Figure 1I) is a diterpenoid isolated from Rabdosia rubescens (Hemsl.) Hara (Donglingcao), with its dry raw herb consisting of up to 0.35% of oridonin. Rabdosia rubescens (Hemsl.) Hara has long been used to treat sore throat, tonsillitis, and esophageal cancer by native residents of Henan Province. Oridonin was included in the Chinese Pharmacopoeia in 1977. Main chemical constituents of Rabdosia rubescens (Hemsl.) Hara are ent-Kaurene diterpenoids, which have multiple biological activities, such as anti-inflammatory, anti-bacterial and anti-tumor effects.

32Oridonin significantly inhibits tumor cell proliferation, induces cell cycle arrest and promotes cell death. In anti-proliferation tests, different cell lines exhibited similar sensitivity to oridonin with an IC50 of about 40-80 μM after 24 hours of treatment. Oridonin induces G2/M cell cycle arrest by up-regulation of heat shock 70 kDa protein 1, serine-threonine kinase receptor-associated protein, translationally controlled tumor protein, stress-induced phosphoprotein 1, trifunctional purine biosynthetic protein adenosine-3 and inorganic pyrophosphatase as well as down-regulation of poly(rC)-binding protein 1 in a p53-independent and p21/Waf1-dependent manner. Induction of apoptosis contributes to oridonin-induced cell death, mainly through mitochondrial-mediated pathways. The up-regulation of Fas, Fas ligand (FasL) and Fas (TNFRSF6)-associated via death domain (FADD) expression, as well as the down-regulation of pro-caspase-8 expression suggests that the activation of the Fas/FasL pathway may also be partially involved in oridonin-induced apoptosis. Possible downstream responses include the induction of loss of mitochondrial transmembrane potential, the activation of several caspases, the down-regulation of Bcl-2, the up-regulation of Bax and Bid as well as the promotion of cytochrome c release and PARP cleavage. However, the regulation of Bcl-xL and participation of caspase-3/9 remain controversial. Oridonin-induced intracellular ROS formation may be an initiator of this process. Other proteins may also be involved in oridonin-induced cell cycle arrest and apoptosis; these proteins include ERK, p38MAPK, insulin-like growth factor 1 receptor, EGFR, NF-κB, as well as p16, p21/Waf1, p27/Kip1 and c-MYC. Oridonin induce cell death by affecting the balance of apoptosis and necrosis. In A375-S2 cells, low concentrations (34.3 μM) of oridonin induce p53 and ERK-dependent apoptosis whereas high concentrations (137.4 μM) induce necrosis. In L929 cells, oridonin induces a caspase-independent and mitochondria- or MAPK-dependent cell death through both apoptosis and necrosis. Similar results are also observed in A431 cells. Oridonin also induces simultaneous autophagy and apoptosis in MCF-7 and HeLa cells. This autophagy may be attributed to the inactivation of Ras, changes in mitochondrial membrane potential, activation of PKC, Raf-1 or c-jun N-terminal kinase (JNK) signaling and even NF-κB signaling pathways. Inhibition of autophagy is attributed to apoptotic up-regulation because oridonin-induced apoptosis augmentation is accompanied by reduced autophagy whereas oridonin-induced autophagy inhibits ROS-mediated apoptosis by activating the p38 MAPK-NF-κB survival pathways in L929 cells. Oridonin inhibits DNA, RNA, and protein syntheses, decrease telomerase, as well as down-regulate human telomerase reverse transcriptase mRNA expression. The in vivo anti-tumor activities of oridonin have been demonstrated in different tumors such as Ehrlich ascites carcinoma, sarcoma-180 solid tumors and in leukemic mice models.

Triptolide

33Triptolide (Figure 1J) is a diterpenoid triepoxide and the principal active ingredient of Tripterygium wilfordii Hook. f. (Leigongteng) used in Chinese medicine to treat inflammation and autoimmune diseases. Triptolide exhibits potent anti-inflammation, immunomodulation and anti-tumor activities. Triptolide exerts multiple effects on apoptosis, angiogenesis, metastasis and drug-resistance.

34Triptolide is active in pro-apoptosis in diverse tumor cell types including ovarian cancer, myeloma, myeloid leukemia, thyroid carcinoma and pancreatic tumor cells. Many in vitro and in vivo studies have tried to elucidate the potential mechanism of triptolide; however, conclusions have been inconsistent. Triptolide seems to induce apoptosis via different pathways in various cell lines. For example, triptolide induces apoptosis by the overexpression of cytomembrane death receptor in a caspase-8-dependent manner in pancreatic tumor and cholangiocarcinoma cells. Triptolide also promotes apoptosis in leukemic and hepatocarcinoma cells by the mitochondrial-mediated pathway.

35Triptolide is a potent inhibitor of tumor angiogenesis in a zebrafish embryo model and demonstrates potent activities against vessel formation by nearly 50% at 1.2 μM. In a xenograft model, triptolide (0.75 mg/kg/day) blocks tumor angiogenesis and progression in a murine tumorigenesis assay possibly correlated with the down-regulation of proangiogenic Tie2 and VEGFR-2 expression. In vitro studies have shown that triptolide inhibits the proliferation of HUVEC. A chick embryo chorioallantoic membrane test shows that triptolide inhibits angiogenesis as well. Triptolide impairs VEGF expression in thyroid carcinoma TA-K cells and down-regulates NF-κB pathway activity; the target genes of triptolide are associated with endothelial cell mobilization in HUVEC. The down-regulation of NF-κB signaling, in combination with the inhibition of VEGF expression, may be the anti-angiogenesis action of triptolide.

36Furthermore, triptolide inhibits tumor metastasis, reducing basal and stimulated colon cancer cell migration through collagen by 65% to 80% and decreasing the expression of VEGF and COX-2. Triptolide inhibits the expression of multiple cytokine receptors potentially involved in cell migration and cancer metastasis, including the thrombin receptor, CXCR4, TNF receptors and TGF-β receptors. Triptolide also inhibits interferon-γ-induced programmed death-1-ligand 1 surface expression whose up-regulation is an important mechanism of tumor immune evasion in human breast cancer cells. Triptolide inhibits the experimental metastasis of melanoma cells to the lungs and spleens of mice. Moreover, triptolide inhibits the migration of lymphoma cells via lymph nodes, a result which may be related to its anti-proliferative effects and blockage of the SDF-1/CXCR4 axis.

37Triptolide enhances the anti-neoplastic activity of chemotherapy. The combination index-isobologram indicates that the effect of triptolide on 5-FU is synergistic on colon carcinoma. In a tumor xenograft model, the combined effects of triptolide (0.25 mg/kg/day) and 5-FU (12 mg/kg/day) on the growth of colon carcinoma are superior to those of individual agents. Triptolide is synergistic with other anti-cancer agents or therapies including hydroxycamptothecin, idarubicin, AraC, TRAIL and ionizing radiation. These results indicate the therapeutic potential of triptolide in treating cancer.

Ursolic acid (UA)

38UA (Figure 1K) is a ubiquitous pentacyclic triterpenoid compound from many plants such as Ligustrum lucidum Ait. (Nuzhen). UA exerts proliferation inhibition in human ovarian cancer CAOV3 cells and doxorubicin-resistant human hepatoma R-HepG2 cells. UA disrupts cell cycle progression and induces necrosis in a clonal MMTV-Wnt-1 mammary tumor cell line. Eight novel UA derivatives with substitutions at positions C-3, C-11, and C-28 of UA show cytotoxicity to some degree in HeLa, SKOV3 and BGC-823 in vitro; only one derivative exhibits more potent cytotoxicity than UA.

39UA induces apoptosis via both extrinsic and intrinsic signaling pathways in cancer cells. In PC-3 cells, UA inhibits proliferation by activating caspase-9 and JNK as well as FasL activation and Akt inhibition. A significant proliferation inhibition and invasion suppression in both a dose- and time-dependent manner is observed in highly metastatic breast cancer MDA-MB-231 cells; this inhibition is related to the down-regulation of MMP2 and u-PA expression. Moreover, UA reduces IL-1β- or TNF-α-induced rat C6 glioma cell invasion and inhibits the interaction of ZIP/p62 and PKC-ζ. Nontoxic UA concentrations inhibit vessel growth in rat aortic ring and down-regulate matrix MMPs such as MMP2 and MMP9. In other cancer cell lines, such as Hep3B, Huh7 and HA22T cells, UA exerts a potential anti-angiogenic effect by decreasing HIF-1α, VEGF and IL-8 gene expression.

Shikonin

40Shikonin (Figure 1L) is a natural anthraquinone derivative isolated from the roots of Lithospermum erythrorhizon (Zicao) and exerts anti-tumor effects mainly by inhibiting cell growth and inducing apoptosis. The underlying molecular mechanisms vary with cell types and treatment methods. Shikonin induces apoptosis in a classic caspase-dependent pathway in cervical, bladder and melanoma cancer cells. Shikonin induces necroptosis regardless of the drug concentration in caspase-3-negative MCF-7 cells. Different concentrations of shikonin induce either apoptosis or necroptosis, and necroptosis converts to apoptosis in the presence of Nec-1 in HL-60 and K562 cells. The growth inhibition and apoptosis induced by shikonin in some cancer cells may be attributed to the inactivation of NF-κB activity or increasing Annexin V signal and CD95 (Fas/APO) expression. Shikonin also induces apoptosis via ROS production in osteosarcoma and Bcr/Abl-positive CML cells.

41Several different mechanisms contribute to the anti-cancer activities of shikonin. For example, shikonin suppresses proteasomal activities thereby inhibiting tumor growth in both H22 allografts and PC-3 xenografts. Shikonin also inhibits topoisomerase II and down-regulates ER2 and activates NFE2-related factor 2 as an anti-estrogen agent in human breast cancer. Shikonin modulates an estrogen enzyme by down-regulating the expression of steroid sulfatase which is important for estrogen biosynthesis. Shikonin inhibits tumor invasion via the NF-κB signaling pathway in human high-metastatic adenoid cystic carcinoma cells. Therefore, shikonin may directly or indirectly inhibit or modulate disease-related cellular targets in cancer.

Emodin

42Emodin (Figure 1M) is a natural anthraquinone derivative isolated from Rheum palmatum L. (Zhangyedahuang), with its dry raw herb consisting of up to 0.20 mg/100 mg of emodin. Emodin exerts anti-tumor activity against various human cancers. Emodin induces cell cycle arrest and apoptosis in cancer cells and the oxidative injury acts upstream of anti-proliferation. Emodin inhibits IL-6-induced Janus-activated kinase 2/STAT3 pathways and induces apoptosis in myeloma cells via the down-regulation of Mcl-1. Emodin down-regulates androgen receptors and inhibits prostate cancer cell growth. Moreover, emodin stabilizes topoisomerase II-DNA cleavage complexes, thereby inducing DNA double-strand breaks. The suppression of excision repair cross complementation 1 (ERCC1) and Rad51 expression through ERK1/2 inactivation is vital in emodin-induced cytotoxicity in human NSCLC cells.

43Emodin inhibits basic fibroblast growth factor (bFGF)-induced proliferation and migration in HUVEC and VEGF-A-induced tube formation. Emodin inhibits tumor cell migration through suppression of the phosphatidylinositol 3-kinase-Cdc42/Rac1 pathway. The disruption of the membrane lipid raft-associated integrin signaling pathway by emodin may inhibit cell adhesion and spreading.

44Emodin sensitizes chemotherapy associated with ROS production. In combined use with cisplatin, emodin elevates ROS generation and enhances chemosensitivity in DU-145 cells, accompanied by the down-regulation of MDR1 expression and suppression of HIF-1α transactivation. Emodin enhances the sensitivity of gallbladder cancer SGC996 cells to platinum drugs via glutathione depletion and multidrug resistance-related protein 1 down-regulation. The mechanisms of the synergistic effects of emodin with cisplatin or gencitabin may be attributed to the emodin-induced down-regulation of ERCC1 and Rad51 expression, respectively. These results suggest that emodin may be used as an adjuvant to enhance the anti-cancer effects of chemotherapeutic agents.

Ginsenoside Rg3

45Extracted from Panax ginseng C.A. Mey. (Renshen) and Panax quinquefolius L., Araliaceae (Xiyangshen), ginsenoside Rg3 (Figure 1N) is a biologically active component with both in vitro and in vivo anti-cancer activities. The anti-proliferative mechanism of ginsenoside Rg3 is associated with the inactivation of NF-κB, modulation of MAPKs and the down-regulation of Wnt/β-catenin signaling. Ginsenoside Rg3 affects the ephrin receptor pathway in HCT-116 human colorectal cancer cells. The anti-proliferative mechanism of ginsenoside Rg3 is also associated with the molecules of mitotic inhibition, DNA replication, repair, and growth factor signaling.

46Ginsenoside Rg3 inhibits the proliferation of HUVEC and suppresses the capillary tube formation of HUVEC on a matrigel at nanomole scales in the presence or absence of VEGF. Ginsenoside Rg3 attenuates VEGF-induced chemo-invasion of HUVEC and ex vivo microvascular sprouting in rat aortic ring. bFGF-induced angiogenesis may be abolished by ginsenoside Rg3. In lung metastasis models of ovarian cancer, ginsenoside Rg3 decreases the number of tumor colonies in the lung and vessels oriented toward the tumor mass. This effect may be partially due to the inhibition of angiogenesis and the decrease in MMP9 expression.

47Ginsenoside Rg3 increases the efficacy of cancer chemotherapy. Combined treatments with ginsenoside Rg3 enhance the susceptibility of colon cancer cells to docetaxel, paclitaxel, cisplatin and doxorubicin; the mechanism of such an enhancement is related to the inhibition of the constitutively activated NF-κB. A similar phenomenon has been observed in prostate cancer cells, in which the combination of ginsenoside Rg3 and docetaxel more effectively induces apoptosis and G1 cell cycle arrest, accompanied by the inhibition of NF-κB activity. Low-dose administration of cyclophosphamide (CTX) with ginsenoside Rg3 increases the efficacy of targeting the tumor microvasculature and the two-drug combination treatment results demonstrate the longest patient survival rates. Ginsenoside Rg3 combined with gemcitabine not only enhances the efficacy of tumor growth suppression and survival prolongation, but also decreases VEGF expression and microvessel density in tumors.

Conclusion

48Natural products such as GA, curcumin, β-elemene et al. derived from Chinese medicinal herbs are potential candidates for anti-cancer therapeutic drugs.

Abbreviations

495-FU: 5-fluorouracil; AIF: apoptosis inducing factor; AP-1: activator protein-1; ARTs: artemisinin and its derivatives; ATRA: all-trans retinoic acid; bFGF: basic fibroblast growth factor; CDKs: cyclin-dependent kinases; CTX: cyclophosphamide DHA: dihydroartemisinin; DPD: dihydropyrimidine dehydrogenase; EGFR: epidermal growth factor receptor; ERK1/2: extracellular signal-regulated kinase 1/2; FasL: Fas ligand; GA: gambogic acid; HDMEC: human dermal microvascular endothelial cells; HUVEC: human umbilical vascular endothelial cells; ICAM-1: intercellular cell adhesion molecule-1; IL-1β: interleukin-1β; LC3: light chain 3; MMP2: matrix metalloproteinase-2; MMP9: matrix metalloproteinase9; MRP1: multidrug resistance-associated protein 1; NF-κB: nuclear factor-kappa B; P-gp: P-glycoprotein; PI3K: phosphoinositide 3-kinase; ROS: reactive oxygen species; STAT: signal transducer and activator of transcription; STS: steroid sulfatase; TfR: transferrin receptor; TPA: 12-O-tetradeca noylphorbol-13-acetate; TRAMP: transgenic adenocarcinoma of the mouse prostate; UA: ursolic acid; u-PA: urokinase plasminogen activators; VCAM-1: vascular cell adhesion molecule-1; VEGF: vascular endothelial growth factor; VEGFR1:vascular endothelial growth factor receptor 1; VEGFR2: vascular endothelial growth factor receptor 2.

Competing interests

50The authors declare that they have no competing interests.

Authors' contributions

51WT, JJL, MQH, YBL, MWC, GSW, JG, ZFZ, ZTX, YYD and XPC wrote the manuscript (WT wrote berberine; JJL wrote GA and ARTs; MQH wrote emodin and ginsenoside Rg3; YBL wrote cucurmin; MWC wrote silibinin; GSW wrote shikonin; JG wrote wogonin; ZFZ wrote β-elemene; ZTX wrote triptolide; YYD wrote UA; XPC wrote oridonin). JJG drew the chemical structures in Figure 1. WT, JJL and XPC revised the manuscript. YTW designed and supervised this work. All authors read and approved the final version of the manuscript.

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85.
Tian X Song Y Dong H Ye B Interaction of anticancer herbal drug berberine with DNA immobilized on the glassy carbon electrodeBioelectrochemistry2008 731822
Not in our library10.1016/j.bioelechem.2008.02.005
86.
Serafim TL Oliveira PJ Sardao VA Perkins E Parke D Holy J Different concentrations of berberine result in distinct cellular localization patterns and cell cycle effects in a melanoma cell lineCancer Chemother Pharmacol2008 6110071018
Not in our library10.1007/s00280-007-0558-9
87.
Kim JB Yu JH Ko E Lee KW Song AK Park SY Shin I Han W Noh DY The alkaloid Berberine inhibits the growth of Anoikis-resistant MCF-7 and MDA-MB-231 breast cancer cell lines by inducing cell cycle arrestPhytomedicine2010 17436440
Not in our library10.1016/j.phymed.2009.08.012
88.
Eom KS Hong JM Youn MJ So HS Park R Kim JM Kim TY Berberine induces G1 arrest and apoptosis in human glioblastoma T98G cells through mitochondrial/caspases pathwayBiol Pharm Bull2008 31558562
Not in our library10.1248/bpb.31.558
89.
Pereira CV Machado NG Oliveira PJ Mechanisms of berberine (natural yellow 18)-induced mitochondrial dysfunction: interaction with the adenine nucleotide translocatorToxicol Sci2008 105408417
Not in our library10.1093/toxsci/kfn131
90.
Wang N Feng Y Zhu M Tsang CM Man K Tong Y Tsao SW Berberine induces autophagic cell death and mitochondrial apoptosis in liver cancer cells: the cellular mechanismJ Cell Biochem2010 11114261436
Not in our library10.1002/jcb.22869
91.
Peng PL Kuo WH Tseng HC Chou FP Synergistic tumor-killing effect of radiation and berberine combined treatment in lung cancer: the contribution of autophagic cell deathInt J Radiat Oncol Biol Phys2008 70529542
Not in our library10.1016/j.ijrobp.2007.08.034
92.
Singh T Vaid M Katiyar N Sharma S Katiyar SK Berberine, an isoquinoline alkaloid, inhibits melanoma cancer cell migration by reducing the expressions of cyclooxygenase-2, prostaglandin E and prostaglandin E receptorsCarcinogenesis2011 328692
Not in our library10.1093/carcin/bgq215
93.
Tsang CM Lau EP Di K Cheung PY Hau PM Ching YP Wong YC Cheung AL Wan TS Tong Y Tsao SW Feng Y Berberine inhibits Rho GTPases and cell migration at low doses but induces G2 arrest and apoptosis at high doses in human cancer cellsInt J Mol Med2009 24131138
Not in our library10.3892/ijmm_00000216
94.
Tang F Wang D Duan C Huang D Wu Y Chen Y Wang W Xie C Meng J Wang L Wu B Liu S Tian D Zhu F He Z Deng F Cao Y Berberine inhibits metastasis of nasopharyngeal carcinoma 5-8F cells by targeting Rho kinase-mediated Ezrin phosphorylation at threonine 567J Biol Chem2009 2842745627466
Not in our library10.1074/jbc.m109.033795
95.
Lin TH Kuo HC Chou FP Lu FJ Berberine enhances inhibition of glioma tumor cell migration and invasiveness mediated by arsenic trioxideBMC Cancer2008 858
Not in our library10.1186/1471-2407-8-58
96.
Kim DW Ahan SH Kim TY Enhancement of Arsenic Trioxide (As(2)O(3))- Mediated Apoptosis Using Berberine in Human Neuroblastoma SH-SY5Y CellsJ Korean Neurosurg Soc2007 42392399
Not in our library10.3340/jkns.2007.42.5.392
97.
Youn MJ So HS Cho HJ Kim HJ Kim Y Lee JH Sohn JS Kim YK Chung SY Park R Berberine, a natural product, combined with cisplatin enhanced apoptosis through a mitochondria/caspase-mediated pathway in HeLa cellsBiol Pharm Bull2008 31789795
Not in our library10.1248/bpb.31.789
98.
Hur JM Hyun MS Lim SY Lee WY Kim D The combination of berberine and irradiation enhances anti-cancer effects via activation of p38 MAPK pathway and ROS generation in human hepatoma cellsJ Cell Biochem2009 107955964
Not in our library10.1002/jcb.22198
99.
Zhang X Gu L Li J Shah N He J Yang L Hu Q Zhou M Degradation of MDM2 by the interaction between berberine and DAXX leads to potent apoptosis in MDM2-overexpressing cancer cellsCancer Res2010 7098959904
Not in our library10.1158/0008-5472.can-10-1546
100.
Gui SY Wu L Peng DY Liu QY Yin BP Shen JZ Preparation and evaluation of a microemulsion for oral delivery of berberinePharmazie2008 63516519
Not in our library
101.
Cheng Z Chen AF Wu F Sheng L Zhang HK Gu M Li YY Zhang LN Hu LH Li JY Li J 8,8-Dimethyldihydroberberine with improved bioavailability and oral efficacy on obese and diabetic mouse modelsBioorg Med Chem2010 1859155924
Not in our library10.1016/j.bmc.2010.06.085
102.
Pan GY Wang GJ Liu XD Fawcett JP Xie YY The involvement of P-glycoprotein in berberine absorptionPharmacol Toxicol2002 91193197
Not in our library10.1034/j.1600-0773.2002.t01-1-910403.x
103.
Hou J Wang D Zhang R Wang H Experimental therapy of hepatoma with artemisinin and its derivatives: in vitro and in vivo activity, chemosensitization, and mechanisms of actionClin Cancer Res2008 1455195530
Not in our library10.1158/1078-0432.ccr-08-0197
104.
Lu JJ Meng LH Cai YJ Chen Q Tong LJ Lin LP Ding J Dihydroartemisinin induces apoptosis in HL-60 leukemia cells dependent of iron and p38 mitogen-activated protein kinase activation but independent of reactive oxygen speciesCancer Biol Ther2008 710171023
Not in our library10.4161/cbt.7.7.6035
105.
Efferth T Sauerbrey A Olbrich A Gebhart E Rauch P Weber HO Hengstler JG Halatsch ME Volm M Tew KD Ross DD Funk JO Molecular modes of action of artesunate in tumor cell linesMol Pharmacol2003 64382394
Not in our library10.1124/mol.64.2.382
106.
Lu JJ Meng LH Shankavaram UT Zhu CH Tong LJ Chen G Lin LP Weinstein JN Ding J Dihydroartemisinin accelerates c-MYC oncoprotein degradation and induces apoptosis in c-MYC-overexpressing tumor cellsBiochem Pharmacol2010 802230
Not in our library10.1016/j.bcp.2010.02.016
107.
Chen H Sun B Pan S Jiang H Sun X Dihydroartemisinin inhibits growth of pancreatic cancer cells in vitro and in vivoAnticancer Drugs2009 20131140
Not in our library10.1097/cad.0b013e3283212ade
108.
Li LN Zhang HD Yuan SJ Tian ZY Wang L Sun ZX Artesunate attenuates the growth of human colorectal carcinoma and inhibits hyperactive Wnt/beta-catenin pathwayInt J Cancer2007 12113601365
Not in our library10.1002/ijc.22804
109.
Du JH Zhang HD Ma ZJ Ji KM Artesunate induces oncosis-like cell death in vitro and has antitumor activity against pancreatic cancer xenografts in vivoCancer Chemother Pharmacol2010 65895902
Not in our library10.1007/s00280-009-1095-5
110.
Mercer AE Copple IM Maggs JL O'Neill PM Park BK The role of heme and the mitochondrion in the chemical and molecular mechanisms of mammalian cell death induced by the artemisinin antimalarialsJ Biol Chem2011 286987996
Not in our library10.1074/jbc.m110.144188
111.
Zhang S Chen H Gerhard GS Heme synthesis increases artemisinin -induced radical formation and cytotoxicity that can be suppressed by superoxide scavengersChem Biol Interact2010 1863035
Not in our library10.1016/j.cbi.2010.03.021
112.
Heme mediates cytotoxicity from artemisinin and serves as a general anti-proliferation target. · 2009
Not checked
113.
Efferth T Benakis A Romero MR Tomicic M Rauh R Steinbach D Hafer R Stamminger T Oesch F Kaina B Marschall M Enhancement of cytotoxicity of artemisinins toward cancer cells by ferrous ironFree Radic Biol Med2004 379981009
Not in our library10.1016/j.freeradbiomed.2004.06.023
114.
Kelter G Steinbach D Konkimalla VB Tahara T Taketani S Fiebig HH Efferth T Role of transferrin receptor and the ABC transporters ABCB6 and ABCB7 for resistance and differentiation of tumor cells towards artesunatePLoS ONE2007 2e798
Not in our library10.1371/journal.pone.0000798
115.
Lu JJ Chen SM Zhang XW Ding J Meng LH The anti-cancer activity of dihydroartemisinin is associated with induction of iron-dependent endoplasmic reticulum stress in colorectal carcinoma HCT116 cellsInvest New Drugs2010 in press
Not in our library10.1007/s10637-010-9481-8
116.
Stockwin LH Han B Yu SX Hollingshead MG ElSohly MA Gul W Slade D Galal AM Newton DL Bumke MA Artemisinin dimer anticancer activity correlates with heme-catalyzed reactive oxygen species generation and endoplasmic reticulum stress inductionInt J Cancer2009 12512661275
Not in our library10.1002/ijc.24496
117.
Jiao Y Ge CM Meng QH Cao JP Tong J Fan SJ Dihydroartemisinin is an inhibitor of ovarian cancer cell growthActa pharmacol Sin2007 2810451056
Not in our library10.1111/j.1745-7254.2007.00612.x
118.
Handrick R Ontikatze T Bauer KD Freier F Rubel A Durig J Belka C Jendrossek V Dihydroartemisinin induces apoptosis by a Bak-dependent intrinsic pathwayMol Cancer Ther2010 924972510
Not in our library10.1158/1535-7163.mct-10-0051
119.
Chen T Li M Zhang R Wang H Dihydroartemisinin induces apoptosis and sensitizes human ovarian cancer cells to carboplatin therapyJ Cell Mol Med2009 1313581370
Not in our library10.1111/j.1582-4934.2008.00360.x
120.
He Q Shi J Shen XL An J Sun H Wang L Hu YJ Sun Q Fu LC Sheikh MS Huang Y Dihydroartemisinin upregulates death receptor 5 expression and cooperates with TRAIL to induce apoptosis in human prostate cancer cellsCancer Biol Ther2010 9819824
Not in our library10.4161/cbt.9.10.11552
121.
Zhou HJ Wang WQ Wu GD Lee J Li A Artesunate inhibits angiogenesis and downregulates vascular endothelial growth factor expression in chronic myeloid leukemia K562 cellsVascul Pharmacol2007 47131138
Not in our library10.1016/j.vph.2007.05.002
122.
Chen HH Zhou HJ Wang WQ Wu GD Antimalarial dihydroartemisinin also inhibits angiogenesisCancer Chemother Pharmacol2004 53423432
Not in our library10.1007/s00280-003-0751-4
123.
Anfosso L Efferth T Albini A Pfeffer U Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisininsPharmacogenomics J2006 6269278
Not in our library10.1038/sj.tpj.6500371
124.
Lee J Zhou HJ Wu XH Dihydroartemisinin downregulates vascular endothelial growth factor expression and induces apoptosis in chronic myeloid leukemia K562 cellsCancer Chemother Pharmacol2006 57213220
Not in our library10.1007/s00280-005-0002-y
125.
Buommino E Baroni A Canozo N Petrazzuolo M Nicoletti R Vozza A Tufano MA Artemisinin reduces human melanoma cell migration by down-regulating alpha V beta 3 integrin and reducing metalloproteinase 2 productionInvest New Drugs2009 27412418
Not in our library10.1007/s10637-008-9188-2
126.
Rasheed SA Efferth T Asangani IA Allgayer H First evidence that the antimalarial drug artesunate inhibits invasion and in vivo metastasis in lung cancer by targeting essential extracellular proteasesInt J Cancer2010 12714751485
Not in our library10.1002/ijc.25315
127.
Efferth T Ramirez T Gebhart E Halatsch ME Combination treatment of glioblastoma multiforme cell lines with the anti-malarial artesunate and the epidermal growth factor receptor tyrosine kinase inhibitor OSI-774Biochem Pharmacol2004 6716891700
Not in our library10.1016/j.bcp.2003.12.035
128.
Li QQ Wang GD Huang FR Banda M Reed E Antineoplastic effect of beta-elemene on prostate cancer cells and other types of solid tumour cellsJ Pharm Pharmacol2010 6210181027
Not in our library10.1111/j.2042-7158.2010.01135.x
129.
Wang G Li X Huang F Zhao J Ding H Cunningham C Coad JE Flynn DC Reed E Li QQ Antitumor effect of beta-elemene in non-small-cell lung cancer cells is mediated via induction of cell cycle arrest and apoptotic cell deathCell Mol Life Sci2005 62881893
Not in our library10.1007/s00018-005-5017-3
130.
Li X Wang G Zhao J Ding H Cunningham C Chen F Flynn DC Reed E Li QQ Antiproliferative effect of beta-elemene in chemoresistant ovarian carcinoma cells is mediated through arrest of the cell cycle at the G2-M phaseCell Mol Life Sci2005 62894904
Not in our library10.1007/s00018-005-5027-1
131.
Zhao J Li QQ Zou B Wang G Li X Kim JE Cuff CF Huang L Reed E Gardner K In vitro combination characterization of the new anticancer plant drug beta-elemene with taxanes against human lung carcinomaInter J Oncol2007 31241252
Not in our library
132.
Yao YQ Ding X Jia YC Huang CX Wang YZ Xu YH Anti-tumor effect of beta-elemene in glioblastoma cells depends on p38 MAPK activationCancer Lett2008 264127134
Not in our library10.1016/j.canlet.2008.01.049
133.
Tao L Zhou L Zheng L Yao M Elemene displays anti-cancer ability on laryngeal cancer cells in vitro and in vivoCancer Chemother Pharmacol2006 582434
Not in our library10.1007/s00280-005-0137-x
134.
Wu XS Xie T Lin J Fan HZ Huang-Fu HJ Ni LF Yan HF An investigation of the ability of elemene to pass through the blood-brain barrier and its effect on brain carcinomasJ Pharm Pharmacol2009 6116531656
Not in our library10.1211/jpp/61.12.0010
135.
Liao WL Du Z Zhang T Guo XL Wen YT Yu Q Luo AQ Li WM Qualitative and quantitative evaluation of Rabdosia Rubescens (Hemls.) Hara of different areasCentral South Pharmacy2010 12912915
Not in our library
136.
Liu JJ Huang RW Lin DJ Wu XY Peng J Pan XL Lin Q Hou M Zhang MH Chen F Antiproliferation effects of oridonin on HPB-ALL cells and its mechanisms of actionAm J Hematol2006 818694
Not in our library10.1002/ajh.20524
137.
Liu JJ Huang RW Lin DJ Peng J Wu XY Pan XL Li MQ Lin Q Anti-proliferative effects of oridonin on SPC-A-1 cells and its mechanism of actionJ Int Med Res2004 32617625
Not in our library10.1177/147323000403200606
138.
Cui Q Tashiro S Onodera S Ikejima T Augmentation of oridonin-induced apoptosis observed with reduced autophagyJ Pharmacol Sci2006 101230239
Not in our library10.1254/jphs.fpj06003x
139.
Wu JN Huang J Yang J Tashiro S Onodera S Ikejima T Caspase inhibition augmented oridonin-induced cell death in murine fibrosarcoma l929 by enhancing reactive oxygen species generationJ Pharmacol Sci2008 1083239
Not in our library10.1254/jphs.fp0072079
140.
Kang N Zhang JH Qiu F Tashiro S Onodera S Ikejima T Inhibition of EGFR signaling augments oridonin-induced apoptosis in human laryngeal cancer cells via enhancing oxidative stress coincident with activation of both the intrinsic and extrinsic apoptotic pathwaysCancer Lett2010 294147158
Not in our library10.1016/j.canlet.2010.01.032
141.
Zhang Y Wu Y Tashiro S Onodera S Ikejima T Involvement of PKC signal pathways in oridonin-induced autophagy in HeLa cells: a protective mechanism against apoptosisBiochem Biophys Res Commun2009 378273278
Not in our library10.1016/j.bbrc.2008.11.038
142.
Wang H Ye Y Pan SY Zhu GY Li YW Fong DW Yu ZL Proteomic identification of proteins involved in the anticancer activities of oridonin in HepG2 cellsPhytomedicine2011 18163169
Not in our library10.1016/j.phymed.2010.06.011
143.
Kang N Zhang JH Qiu F Chen S Tashiro S Onodera S Ikejima T Induction of G(2)/M phase arrest and apoptosis by oridonin in human laryngeal carcinoma cellsJ Nat Prod2010 7310581063
Not in our library10.1021/np9008199
144.
Liu YQ Mu ZQ You S Tashiro S Onodera S Ikejima T Fas/FasL signaling allows extracelluar-signal regulated kinase to regulate cytochrome c release in oridonin-induced apoptotic U937 cellsBiol Pharm Bull2006 2918731879
Not in our library10.1248/bpb.29.1873
145.
Li D Wu LJ Tashiro S Onodera S Ikejima T Oridonin induces human epidermoid carcinoma A431 cell apoptosis through tyrosine kinase and mitochondrial pathwayJ Asian Nat Prod Res2008 107787
Not in our library10.1080/10286020701273866
146.
Zhang CL Wu LJ Tashiro S Onodera S Ikejima T Oridonin induced A375-S2 cell apoptosis via bax-regulated caspase pathway activation, dependent on the cytochrome c/caspase-9 apoptosomeJ Asian Nat Prod Res2004 6127138
Not in our library10.1080/1028602031000147375
147.
Zhang CL Wu LJ Zuo HJ Tashiro S Onodera S Ikejima T Cytochrome c release from oridonin-treated apoptotic A375-S2 cells is dependent on p53 and extracellular signal-regulated kinase activationJ Pharmacol Sci2004 96155163
Not in our library10.1254/jphs.fpj04008x
148.
Liu J Huang R Lin D Wu X Peng J Lin Q Pan X Zhang M Hou M Chen F Apoptotic effect of oridonin on NB4 cells and its mechanismLeuk Lymphoma2005 46593597
Not in our library10.1080/10428190400019800
149.
Zhang CL Wu LJ Tashiro S Onodera S Ikejima T Oridonin induces a caspase-independent but mitochondria- and MAPK-dependent cell death in the murine fibrosarcoma cell line L929Biol Pharm Bull2004 2715271531
Not in our library10.1248/bpb.27.1527
150.
Cui Q Yu JH Wu JN Tashiro S Onodera S Minami M Ikejima T P53-mediated cell cycle arrest and apoptosis through a caspase-3- independent, but caspase-9-dependent pathway in oridonin-treated MCF-7 human breast cancer cellsActa Pharmacol Sin2007 2810571066
Not in our library10.1111/j.1745-7254.2007.00588.x
151.
Cheng Y Qiu F Ikejima T Molecular mechanisms of oridonin-induced apoptosis and autophagy in murine fibrosarcoma L929 cellsAutophagy2009 5430431
Not in our library10.4161/auto.5.3.7896
152.
Cheng Y Qiu F Ye YC Tashiro S Onodera S Ikejima T Oridonin induces G2/M arrest and apoptosis via activating ERK-p53 apoptotic pathway and inhibiting PTK-Ras-Raf-JNK survival pathway in murine fibrosarcoma L929 cellsArch Biochem Biophys2009 4907075
Not in our library10.1016/j.abb.2009.08.011
153.
Wang HJ Li D Yang FY Tashiro S Onodera S Ikejima T Oridonin induces human melanoma A375-S2 cell death partially through inhibiting insulin-like growth factor 1 receptor signalingJ Asian Nat Prod Res2008 10787798
Not in our library10.1080/10286020802030918
154.
Li D Wu LJ Tashiro S Onodera S Ikejima T Oridonin inhibited the tyrosine kinase activity and induced apoptosis in human epidermoid carcinoma A431 cellsBiol Pharm Bull2007 30254260
Not in our library10.1248/bpb.30.254
155.
Ikezoe T Yang Y Bandobashi K Saito T Takemoto S Machida H Togitani K Koeffler HP Taguchi H Oridonin, a diterpenoid purified from Rabdosia rubescens, inhibits the proliferation of cells from lymphoid malignancies in association with blockade of the NF-kappa B signal pathwaysMol Cancer Ther2005 4578586
Not in our library10.1158/1535-7163.mct-04-0277
156.
Gao FH Hu XH Li W Liu H Zhang YJ Guo ZY Xu MH Wang ST Jiang B Liu F Zhao YZ Fang Y Chen FY Wu YL Oridonin induces apoptosis and senescence in colorectal cancer cells by increasing histone hyperacetylation and regulation of p16, p21, p27 and c-mycBMC Cancer2010 10610
Not in our library10.1186/1471-2407-10-610
157.
Cui Q Tashiro S Onodera S Minami M Ikejima T Autophagy preceded apoptosis in oridonin-treated human breast cancer MCF-7 cellsBiol Pharm Bull2007 30859864
Not in our library10.1248/bpb.30.859
158.
Li D Cui Q Chen SG Wu LJ Tashiro S Onodera S Ikejima T Inactivation of ras and changes of mitochondrial membrane potential contribute to oridonin-induced autophagy in a431 cellsJ Pharmacol Sci2007 1052233
Not in our library10.1254/jphs.fpj06022x
159.
Zhang Y Wu Y Wu D Tashiro S Onodera S Ikejima T NF-kappab facilitates oridonin-induced apoptosis and autophagy in HT1080 cells through a p53-mediated pathwayArch Biochem Biophys2009 4892533
Not in our library10.1016/j.abb.2009.07.017
160.
Cheng Y Qiu F Ye YC Guo ZM Tashiro S Onodera S Ikejima T Autophagy inhibits reactive oxygen species-mediated apoptosis via activating p38-nuclear factor-kappa B survival pathways in oridonin-treated murine fibrosarcoma L929 cellsFEBS J2009 27612911306
Not in our library10.1111/j.1742-4658.2008.06864.x
161.
Wang MY Lin C Zhang TM Effects of oridonin on DNA, RNA and protein syntheses of leukemia L 1210 cells studied by autoradiographyZhongguo Yao Li Xue Bao1987 8164165
Not in our library
162.
Liu JJ Wu XY Peng J Pan XL Lu HL Antiproliferation effects of oridonin on HL-60 cellsAnn Hematol2004 83691695
Not in our library10.1007/s00277-004-0919-y
163.
Lou H Zhang X Gao L Feng F Wang J Wei X Yu Z Zhang D Zhang Q In vitro and in vivo antitumor activity of oridonin nanosuspensionInt J Pharm2009 379181186
Not in our library10.1016/j.ijpharm.2009.06.022
164.
Zhou GB Kang H Wang L Gao L Liu P Xie J Zhang FX Weng XQ Shen ZX Chen J Gu LJ Yan M Zhang DE Chen SJ Wang ZY Chen Z Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivoBlood2007 10934413450
Not in our library10.1182/blood-2006-06-032250
165.
He MF Liu L Ge W Shaw PC Jiang R Wu LW But PP Antiangiogenic activity of Tripterygium wilfordii and its terpenoidsJ Ethnopharmacol2009 1216168
Not in our library10.1016/j.jep.2008.09.033
166.
Li H Takai N Yuge A Furukawa Y Tsuno A Tsukamoto Y Kong S Moriyama M Narahara H Novel target genes responsive to the anti-growth activity of triptolide in endometrial and ovarian cancer cellsCancer Lett2010 297198206
Not in our library10.1016/j.canlet.2010.05.012
167.
Zhao F Chen Y Zeng L Li R Zeng R Wen L Liu Y Zhang C Role of triptolide in cell proliferation, cell cycle arrest, apoptosis and histone methylation in multiple myeloma U266 cellsEur J Pharmacol2010 646111
Not in our library10.1016/j.ejphar.2010.05.034
168.
Zhou GS Hu Z Fang HT Zhang FX Pan XF Chen XQ Hu AM Xu L Zhou GB Biologic activity of triptolide in t(8;21) acute myeloid leukemia cellsLeuk Res2011 35214218
Not in our library10.1016/j.leukres.2010.07.013
169.
Zhu W Hu H Qiu P Yan G Triptolide induces apoptosis in human anaplastic thyroid carcinoma cells by a p53-independent but NF-kappaB- related mechanismOncol Rep2009 2213971401
Not in our library10.3892/or_00000580
170.
Zhou GX Ding XL Huang JF Zhang H Wu SB Suppression of 5-lipoxygenase gene is involved in triptolide-induced apoptosis in pancreatic tumor cell linesBiochim Biophys Acta2007 177010211027
Not in our library10.1016/j.bbagen.2007.03.002
171.
Clawson KA Borja-Cacho D Antonoff MB Saluja AK Vickers SM Triptolide and TRAIL combination enhances apoptosis in cholangiocarcinomaJ Surg Res2010 163244249
Not in our library10.1016/j.jss.2010.03.067
172.
Carter BZ Mak DH Schober WD McQueen T Harris D Estrov Z Evans RL Andreeff M Triptolide induces caspase-dependent cell death mediated via the mitochondrial pathway in leukemic cellsBlood2006 108630637
Not in our library10.1182/blood-2005-09-3898
173.
Wan CK Wang C Cheung HY Yang M Fong WF Triptolide induces Bcl-2 cleavage and mitochondria dependent apoptosis in p53-deficient HL-60 cellsCancer Lett2006 2413141
Not in our library10.1016/j.canlet.2005.10.001
174.
Johnson SM Wang X Mark Evers B Triptolide Inhibits Proliferation and Migration of Colon Cancer Cells by Inhibition of Cell Cycle Regulators and Cytokine ReceptorsJ Surg Res2011 168197205
Not in our library10.1016/j.jss.2009.07.002
175.
Chang HJ Kim MH Baek MK Park JS Chung IJ Shin BA Ahn BW Jung YD Triptolide inhibits tumor promoter-induced uPAR expression via blocking NF-kappaB signaling in human gastric AGS cellsAnticancer Res2007 2734113417
Not in our library
176.
Zhu W He S Li Y Qiu P Shu M Ou Y Zhou Y Leng T Xie J Zheng X Xu D Su X Yan G Anti-angiogenic activity of triptolide in anaplastic thyroid carcinoma is mediated by targeting vascular endothelial and tumor cellsVascul Pharmacol2010 524654
Not in our library10.1016/j.vph.2009.10.006
177.
Liang M Fu J Triptolide inhibits interferon-gamma-induced programmed death-1-ligand 1 surface expression in breast cancer cellsCancer Lett2008 270337341
Not in our library10.1016/j.canlet.2008.05.025
178.
Yang S Chen J Guo Z Xu XM Wang L Pei XF Yang J Underhill CB Zhang L Triptolide inhibits the growth and metastasis of solid tumorsMol Cancer Ther2003 26572
Not in our library
179.
Zhang C Cui GH Liu F Wu QL Chen Y Inhibitory effect of triptolide on lymph node metastasis in patients with non-Hodgkin lymphoma by regulating SDF-1/CXCR4 axis in vitroActa pharmacologica Sinica2006 2714381446
Not in our library10.1111/j.1745-7254.2006.00415.x
180.
Tang XY Zhu YQ Tao WH Wei B Lin XL Synergistic effect of triptolide combined with 5-fluorouracil on colon carcinomaPostgrad Med J2007 83338343
Not in our library10.1136/pgmj.2006.055426
181.
Yang SW Wang W Xie XY Zhu WP Li FQ In vitro synergistic cytotoxic effect of triptolide combined with hydroxycamptothecin on pancreatic cancer cellsAm J Chin Med2011 39121134
Not in our library10.1142/s0192415x11008695
182.
Pigneux A Mahon FX Uhalde M Jeanneteau M Lacombe F Milpied N Reiffers J Belloc F Triptolide cooperates with chemotherapy to induce apoptosis in acute myeloid leukemia cellsExp Hematol2008 3616481659
Not in our library10.1016/j.exphem.2008.08.002
183.
Carter BZ Mak DH Schober WD Dietrich MF Pinilla C Vassilev LT Reed JC Andreeff M Triptolide sensitizes AML cells to TRAIL-induced apoptosis via decrease of XIAP and p53-mediated increase of DR5Blood2008 11137423750
Not in our library10.1182/blood-2007-05-091504
184.
Wang W Yang S Su Y Xiao Z Wang C Li X Lin L Fenton BM Paoni SF Ding I Keng P Okunieff P Zhang L Enhanced antitumor effect of combined triptolide and ionizing radiationClin Cancer Res2007 1348914899
Not in our library10.1158/1078-0432.ccr-07-0416
185.
Wang X Li L Wang B Xiang J Effects of ursolic acid on the proliferation and apoptosis of human ovarian cancer cellsJ Huazhong Uni Sci Technol Med Sci2009 29761764
Not in our library10.1007/s11596-009-0618-y
186.
Yang L Liu X Lu Z Yuet-Wa Chan J Zhou L Fung KP Wu P Wu S Ursolic acid induces doxorubicin-resistant HepG2 cell death via the release of apoptosis-inducing factorCancer Lett2010 298128138
Not in our library10.1016/j.canlet.2010.06.010
187.
De Angel RE Smith SM Glickman RD Perkins SN Hursting SD Antitumor effects of ursolic acid in a mouse model of postmenopausal breast cancerNutr Cancer2010 6210741086
Not in our library10.1080/01635581.2010.492092
188.
Meng Y Song Y Yan Z Xia Y Synthesis and in vitro cytotoxicity of novel ursolic acid derivativesMolecules (Basel, Switzerland)2010 1540334040
Not in our library10.3390/molecules15064033
189.
Kwon SH Park HY Kim JY Jeong IY Lee MK Seo KI Apoptotic action of ursolic acid isolated from Corni fructus in RC-58T/h/SA#4 primary human prostate cancer cellsBioorg Med Chem Lett2010 2064356438
Not in our library10.1016/j.bmcl.2010.09.073
190.
Zhang Y Kong C Zeng Y Wang L Li Z Wang H Xu C Sun Y Ursolic acid induces PC-3 cell apoptosis via activation of JNK and inhibition of Akt pathways in vitroMol Carcinog2010 49374385
Not in our library10.1002/mc.20610
191.
Yeh CT Wu CH Yen GC Ursolic acid, a naturally occurring triterpenoid, suppresses migration and invasion of human breast cancer cells by modulating c-Jun N-terminal kinase, Akt and mammalian target of rapamycin signalingMol Nutr Food Res2010 5412851295
Not in our library10.1002/mnfr.200900414
192.
Huang HC Huang CY Lin-Shiau SY Lin JK Ursolic acid inhibits IL-1beta or TNF-alpha-induced C6 glioma invasion through suppressing the association ZIP/p62 with PKC-zeta and downregulating the MMP-9 expressionMol Carcinog2009 48517531
Not in our library10.1002/mc.20490
193.
Kanjoormana M Kuttan G Antiangiogenic activity of ursolic acidIntegr Cancer Ther2010 9224235
Not in our library10.1177/1534735410367647
194.
Lin CC Huang CY Mong MC Chan CY Yin MC Antiangiogenic Potential of Three Triterpenic Acids in Human Liver Cancer CellsJ Agric Food Chem2010 755762
Not in our library10.1021/jf103904b
195.
Wu Z Wu L Li L Tashiro S Onodera S Ikejima T p53-mediated cell cycle arrest and apoptosis induced by shikonin via a caspase-9-dependent mechanism in human malignant melanoma A375-S2 cellsJ Pharmacol Sci2004 94166176
Not in our library10.1254/jphs.94.166
196.
Wu Z Wu LJ Li LH Tashiro S Onodera S Ikejima T Shikonin regulates HeLa cell death via caspase-3 activation and blockage of DNA synthesisJ Asian Nat Prod Res2004 6155166
Not in our library10.1080/1028602032000169622
197.
Yeh CC Kuo HM Li TM Lin JP Yu FS Lu HF Chung JG Yang JS Shikonin-induced apoptosis involves caspase-3 activity in a human bladder cancer cell line (T24)In Vivo2007 2110111019
Not in our library
198.
Yoon Y Kim YO Lim NY Jeon WK Sung HJ Shikonin, an ingredient of Lithospermum erythrorhizon induced apoptosis in HL60 human premyelocytic leukemia cell linePlanta Med1999 65532535
Not in our library10.1055/s-1999-14010
199.
Han W Li L Qiu S Lu Q Pan Q Gu Y Luo J Hu X Shikonin circumvents cancer drug resistance by induction of a necroptotic deathMol Cancer Ther2007 616411649
Not in our library10.1158/1535-7163.mct-06-0511
200.
Han W Xie J Li L Liu Z Hu X Necrostatin-1 reverts shikonin-induced necroptosis to apoptosisApoptosis2009 14674686
Not in our library10.1007/s10495-009-0334-x
201.
Min R Tong J Wenjun Y Wenhu D Xiaojian Z Jiacai H Jian Z Wantao C Chenping Z Growth inhibition and induction of apoptosis in human oral squamous cell carcinoma Tca-8113 cell lines by Shikonin was partly through the inactivation of NF-kappaB pathwayPhytother Res2008 22407415
Not in our library10.1002/ptr.2340
202.
Nie YK Zhu LS Yu HM Shikonin inhibits the proliferation and induces the apoptosis of human HepG2 cellsCan J Physiol Pharm2010 8811381146
Not in our library10.1139/y10-085
203.
Chang IC Huang YJ Chiang TI Yeh CW Hsu LS Shikonin Induces Apoptosis through Reactive Oxygen Species/Extracellular Signal- Regulated Kinase Pathway in Osteosarcoma CellsBiol Pharm Bull2010 33816824
Not in our library10.1248/bpb.33.816
204.
Mao X Yu CR Li WH Li WX Induction of apoptosis by shikonin through a ROS/JNK-mediated process in Bcr/Abl-positive chronic myelogenous leukemia (CML) cellsCell Res2008 18879888
Not in our library10.1038/cr.2008.86
205.
Yang H Zhou P Huang H Chen D Ma N Cui QC Shen S Dong W Zhang X Lian W Wang X Dou QP Liu J Shikonin exerts antitumor activity via proteasome inhibition and cell death induction in vitro and in vivoInt J Cancer2009 12424502459
Not in our library10.1002/ijc.24195
206.
Yang F Chen Y Duan W Zhang C Zhu H Ding J SH-7, a new synthesized shikonin derivative, exerting its potent antitumor activities as a topoisomerase inhibitorInt J Cancer2006 11911841193
Not in our library10.1002/ijc.21943
207.
Yao Y Zhou Q A novel antiestrogen agent Shikonin inhibits estrogen- dependent gene transcription in human breast cancer cellsBreast Cancer Res Tr2010 121233240
Not in our library10.1007/s10549-009-0547-2
208.
Yao YA Brodie AMH Davidson NE Kensler TW Zhou Q Inhibition of estrogen signaling activates the NRF2 pathway in breast cancerBreast Cancer Res Tr2010 124585591
Not in our library10.1007/s10549-010-1023-8
209.
Min R Zun Z Min Y Wenhu D Wenjun Y Chenping Z Shikonin inhibits tumor invasion via down-regulation of NF-kappaB-mediated MMP-9 expression in human ACC-M cellsOral Dis2011 17362369
Not in our library10.1111/j.1601-0825.2010.01758.x
210.
Wang L Li D Bao C You J Wang Z Shi Y Zhang H Ultrasonic extraction and separation of anthraquinones from Rheum palmatum LUltrason Sonochem2008 15738746
Not in our library10.1016/j.ultsonch.2007.12.008
211.
Srinivas G Babykutty S Sathiadevan PP Srinivas P Molecular mechanism of emodin action: transition from laxative ingredient to an antitumor agentMed Res Rev2007 27591608
Not in our library10.1002/med.20095
212.
Chun-Guang W Jun-Qing Y Bei-Zhong L Dan-Ting J Chong W Liang Z Dan Z Yan W Anti-tumor activity of emodin against human chronic myelocytic leukemia K562 cell lines in vitro and in vivoEur J Pharmacol2010 6273341
Not in our library10.1016/j.ejphar.2009.10.035
213.
Muto A Hori M Sasaki Y Saitoh A Yasuda I Maekawa T Uchida T Asakura K Nakazato T Kaneda T Kizaki M Ikeda Y Yoshida T Emodin has a cytotoxic activity against human multiple myeloma as a Janus-activated kinase 2 inhibitorMol Cancer Ther2007 6987994
Not in our library10.1158/1535-7163.mct-06-0605
214.
Su YT Chang HL Shyue SK Hsu SL Emodin induces apoptosis in human lung adenocarcinoma cells through a reactive oxygen species-dependent mitochondrial signaling pathwayBiochem Pharmacol2005 70229241
Not in our library10.1016/j.bcp.2005.04.026
215.
Cha TL Qiu L Chen CT Wen Y Hung MC Emodin down-regulates androgen receptor and inhibits prostate cancer cell growthCancer Res2005 6522872295
Not in our library10.1158/0008-5472.can-04-3250
216.
Li Y Luan Y Qi X Li M Gong L Xue X Wu X Wu Y Chen M Xing G Yao J Ren Jl Emodin triggers DNA double-strand breaks by stabilizing topoisomerase II-DNA cleavage complexes and by inhibiting ATP hydrolysis of topoisomerase IIToxicol Sci2010 118435443
Not in our library10.1093/toxsci/kfq282
217.
Ko JC Su YJ Lin ST Jhan JY Ciou SC Cheng CM Lin YW Suppression of ERCC1 and Rad51 expression through ERK1/2 inactivation is essential in emodin-mediated cytotoxicity in human non-small cell lung cancer cellsBiochem Pharmacol2010 79655664
Not in our library10.1016/j.bcp.2009.09.024
218.
Kwak HJ Park MJ Park CM Moon SI Yoo DH Lee HC Lee SH Kim MS Lee HW Shin WS Park IC Rhee CH Hong SI Emodin inhibits vascular endothelial growth factor-A-induced angiogenesis by blocking receptor-2 (KDR/Flk-1) phosphorylationInt J Cancer2006 11827112720
Not in our library10.1002/ijc.21641
219.
Huang Q Shen HM Ong CN Emodin inhibits tumor cell migration through suppression of the phosphatidylinositol 3-kinase-Cdc42/Rac1 pathwayCell Mol Life Sci2005 6211671175
Not in our library10.1007/s00018-005-5050-2
220.
Huang Q Shen HM Shui G Wenk MR Ong CN Emodin inhibits tumor cell adhesion through disruption of the membrane lipid Raft-associated integrin signaling pathwayCancer Res2006 6658075815
Not in our library10.1158/0008-5472.can-06-0077
221.
Wang XJ Yang J Cang H Zou YQ Yi J Gene expression alteration during redox-dependent enhancement of arsenic cytotoxicity by emodin in HeLa cellsCell Res2005 15511522
Not in our library10.1038/sj.cr.7290321
222.
Cai J Niu X Chen Y Hu Q Shi G Wu H Wang J Yi J Emodin-induced generation of reactive oxygen species inhibits RhoA activation to sensitize gastric carcinoma cells to anoikisNeoplasia2008 104151
Not in our library10.1593/neo.07754
223.
Huang XZ Wang J Huang C Chen YY Shi GY Hu QS Yi J Emodin enhances cytotoxicity of chemotherapeutic drugs in prostate cancer cells: the mechanisms involve ROS-mediated suppression of multidrug resistance and hypoxia inducible factor-1Cancer Biol Ther2008 7468475
Not in our library10.4161/cbt.7.3.5457
224.
Wang W Sun YP Huang XZ He M Chen YY Shi GY Li H Yi J Wang J Emodin enhances sensitivity of gallbladder cancer cells to platinum drugs via glutathion depletion and MRP1 downregulationBiochem Pharmacol2010 7911341140
Not in our library10.1016/j.bcp.2009.12.006
225.
Chen RS Jhan JY Su YJ Lee WT Cheng CM Ciou SC Lin ST Chuang SM Ko JC Lin YW Emodin enhances gefitinib-induced cytotoxicity via Rad51 downregulation and ERK1/2 inactivationExp Cell Res2009 31526582672
Not in our library10.1016/j.yexcr.2009.06.002
226.
Ko JC Su YJ Lin ST Jhan JY Ciou SC Cheng CM Chiu YF Kuo YH Tsai MS Lin YW Emodin enhances cisplatin-induced cytotoxicity via down- regulation of ERCC1 and inactivation of ERK1/2Lung Cancer2010 69155164
Not in our library10.1016/j.lungcan.2009.10.013
227.
Yue PY Wong DY Wu PK Leung PY Mak NK Yeung HW Liu L Cai Z Jiang ZH Fan TP Wong RN The angiosuppressive effects of 20(R)- ginsenoside Rg3Biochem Pharmacol2006 72437445
Not in our library10.1016/j.bcp.2006.04.034
228.
Inhibitory effect of ginsenoside Rg3 combined with gemcitabine on angiogenesis and growth of lung cancer in mice · 2009
Not checked
229.
Kim SM Lee SY Yuk DY Moon DC Choi SS Kim Y Han SB Oh KW Hong JT Inhibition of NF-kappaB by ginsenoside Rg3 enhances the susceptibility of colon cancer cells to docetaxelArch Pharm Res2009 32755765
Not in our library10.1007/s12272-009-1515-4
230.
Kim SM Lee SY Cho JS Son SM Choi SS Yun YP Yoo HS Yoon do Y Oh KW Han SB Hong JT Combination of ginsenoside Rg3 with docetaxel enhances the susceptibility of prostate cancer cells via inhibition of NF-kappaBEur J Pharmacol2010 63119
Not in our library10.1016/j.ejphar.2009.12.018
231.
Kim HS Lee EH Ko SR Choi KJ Park JH Im DS Effects of ginsenosides Rg3 and Rh2 on the proliferation of prostate cancer cellsArch Pharm Res2004 27429435
Not in our library10.1007/bf02980085
232.
He BC Gao JL Luo X Luo J Shen J Wang L Zhou Q Wang YT Luu HH Haydon RC Wang CZ Du W Yuan CS He TC Zhang BQ Ginsenoside Rg3 inhibits colorectal tumor growth through the down-regulation of Wnt/ß-catenin signalingInt J Oncol2011 38437445
Not in our library10.3892/ijo.2010.858
233.
Luo X Wang CZ Chen J Song WX Luo J Tang N He BC Kang Q Wang Y Du W He TC Yuan CS Characterization of gene expression regulated by American ginseng and ginsenoside Rg3 in human colorectal cancer cellsInt J Oncol2008 32975983
Not in our library
234.
Lee SY Kim GT Roh SH Song JS Kim HJ Hong SS Kwon SW Park JH Proteomic analysis of the anti-cancer effect of 20S-ginsenoside Rg3 in human colon cancer cell linesBiosci Biotechnol Biochem2009 73811816
Not in our library10.1271/bbb.80637
235.
Xu TM Cui MH Xin Y Gu LP Jiang X Su MM Wang DD Wang WJ Inhibitory effect of ginsenoside Rg3 on ovarian cancer metastasisChin Med J (Engl)2008 12113941397
Not in our library
236.
Zhang Q Kang X Zhao W Antiangiogenic effect of low-dose cyclophosphamide combined with ginsenoside Rg3 on Lewis lung carcinomaBiochem Biophys Res Commun2006 342824828
Not in our library10.1016/j.bbrc.2006.02.044

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