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Apoptosis Deregulation and the Development of Cancer Multi-Drug Resistance

Christiana M. Neophytou, Ioannis P. Trougakos, Nuray Erin and 1 more

Cancers · 2021 · Review · CC BY

doi:10.3390/cancers13174363

Abstract

Simple Summary. Despite recent therapeutic advances against cancer, many patients do not respond well or respond poorly, to treatment and develop resistance to more than one anti-cancer drug, a term called multi-drug resistance (MDR). One of the main factors that contribute to MDR is the deregulation of apoptosis or programmed cell death. Herein, we describe the major apoptotic pathways and discuss how pro-apoptotic and anti-apoptotic proteins are modified in cancer cells to convey drug resistance. We also focus on our current understanding related to the interactions between survival and cell death pathways, as well as on mechanisms underlying the balance shift towards cancer cell growth and drug resistance. Moreover, we highlight the role of the tumor microenvironment components in blocking apoptosis in MDR tumors, and we discuss the significance and potential exploitation of epigenetic modifications for cancer treatment. Finally, we summarize the current and future therapeutic approaches for overcoming MDR.

Abstract. The ability of tumor cells to evade apoptosis is established as one of the hallmarks of cancer. The deregulation of apoptotic pathways conveys a survival advantage enabling cancer cells to develop multi-drug resistance (MDR), a complex tumor phenotype referring to concurrent resistance toward agents with different function and/or structure. Proteins implicated in the intrinsic pathway of apoptosis, including the Bcl-2 superfamily and Inhibitors of Apoptosis (IAP) family members, as well as their regulator, tumor suppressor p53, have been implicated in the development of MDR in many cancer types. The PI3K/AKT pathway is pivotal in promoting survival and proliferation and is often overactive in MDR tumors. In addition, the tumor microenvironment, particularly factors secreted by cancer-associated fibroblasts, can inhibit apoptosis in cancer cells and reduce the effectiveness of different anti-cancer drugs. In this review, we describe the main alterations that occur in apoptosis-and related pathways to promote MDR. We also summarize the main therapeutic approaches against resistant tumors, including agents targeting Bcl-2 family members, small molecule inhibitors against IAPs or AKT and agents of natural origin that may be used as monotherapy or in combination with conventional therapeutics. Finally, we highlight the potential of therapeutic exploitation of epigenetic modifications to reverse the MDR phenotype.

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.

1. Introduction

Novel diagnostic and cancer therapeutic technologies have improved patient response to treatment and have lowered mortality rates. However, in several cases, the 5-year survival rate remains low, mostly due to the intrinsic resistance or to the development of acquired resistance to anticancer drugs. Multi-drug resistance (MDR) refers to the state in which cancer cells become resistant to two or more drugs that have entirely different mechanisms of action and/or chemical structures. Thus, different cancer types become difficult to treat because of MDR. These mainly include breast, lung, colorectal and prostate cancer that represent the most frequently occurring malignancies with the highest mortality rates.

A variety of factors and mechanisms promote the development of MDR in cancer cells, including drug inactivation, detoxification mechanisms, increased drug efflux, mutations in genes encoding drug targets, epigenetic changes, deregulation of DNA damage/repair processes, contribution of cancer stem cells, increased tumor heterogeneity, involvement of the tumor microenvironment (TME), epithelial to mesenchymal transition (EMT), modulation of reactive oxygen species (ROS) and inhibition of cell death pathways. Evasion of apoptosis or programmed cell death (PCD) has been well established as a one of the major hallmarks of cancer. Deregulation of apoptotic pathways can lead to tumorigenesis, autoimmune and degenerative diseases. In this review, we focus on the deregulation of apoptotic pathways and the development of multi-drug resistance in a variety of tumor types. We also discuss the role of the TME in regulating apoptosis in MDR tumors, as well as current and future therapeutic approaches targeting apoptosis that are being developed to overcome cancer MDR. Finally, we discuss the potential exploitation of epigenetic modifications for new therapeutic advances.

2. Overview of Apoptotic Pathways

Apoptosis is a tightly controlled physiological process, necessary for normal embryonic development, preservation of genome integrity, proper function of the immune system and maintenance of tissue homeostasis. Apoptosis may be induced by a variety of agents, including low doses of radiation, hypoxia, heat, cytotoxic drugs or more specialized anti-cancer molecules. The apoptotic process does not induce inflammation as the cell contents are eventually absorbed by phagocytic cells.

Two main pathways contribute to apoptosis, i.e., (a) the intrinsic or mitochondrial pathway that is mostly activated by intracellular stress signals, including oxidative stress and (b) the extrinsic or death receptor pathway that is engaged following extracellular signals. The latter is induced following binding of death ligands to the extracellular domain of death receptors which (among others) include Receptor 1/Tumor Necrosis Factor-α (TNFR1/TNF-α) and Fas Receptor/Fas Ligand (FasR/FasL). Downstream to this binding, death receptors establish homotrimer structures followed by self-assembly of their intracellular parts that contain death domains (DDs). The intracellular domains of the TNF or FAS receptors then recruit adaptor proteins, including the TNFR1-associated death domain protein (TRADD) and FAS-associated death domain protein (FADD), respectively; adaptor proteins contain the DED protein interaction component, that by recruiting inactive initiator caspase-8 forms the Death Inducing Signaling Complex (DISC) which then triggers caspase-8 activation via oligomerization.

Caspases are cysteinyl, aspartate-specific proteases that play critical roles in apoptosis. They are expressed as inactive pro-enzymes and contain an N-terminal pro-domain and a C-terminal catalytic domain. Their C-terminal domain comprises a p20 large subunit and a p10 small subunit. The so-called initiator caspases (casp-2, -8, -9, -10) are activated in the early stages of apoptosis and induce a cascade of reactions to kickstart the apoptotic process. Executioner caspases (casp-3, -6, -7) are activated during the later stages of the process and are responsible for cleaving cellular components. Structurally, the pro-domain of executioner caspases is very short compared to initiator caspases. Initiator caspases contain in their pro-domain either a death effector domain (DED) (caspases-8 and -10) or a caspase-recruitment domain (CARD) (e.g., caspases-2 and -9). DED is responsible for the interaction of caspases with molecules that regulate their activity. Inactive caspases are activated via cleavage at aspartate residues, while the N-terminal domain is removed by cleavage between the large and small subunits. Initiator caspases then cleave downstream caspases triggering a proteolytic cascade that amplifies the apoptotic signaling pathway.

The intrinsic apoptotic pathway is initiated by different signals, including ultra-violet (UV) or gamma irradiation, hypoxia, growth factors, hormone/cytokine deprivation, viral virulence factors, heat, DNA-damaging agents and the activation of oncogenic factors (Figure 1). Apoptotic signals induce a process called mitochondrial outer membrane permeabilization (MOMP) which involves opening of the mitochondrial permeability transition (MPT) pore and release of pro-apoptotic proteins from the inter-membrane space (IMS) into the cytosol. Once the outer mitochondrial membrane becomes permeable, pro-apoptotic factors located in the inter-membrane mitochondrial space exit towards the cytosol. For example, cytochrome c and Apoptotic protease activating factor 1 (Apaf-1) are released, interact with caspase-9 and activate the latter, while forming a structure known as the apoptosome. Further, Smac/DIABLO and HtrA2/Omi are released and induce apoptosis by inhibiting a group of proteins called Inhibitors of Apoptosis Proteins (IAPs).

MOMP is controlled by Bcl-2 family members. Bcl-2 proteins are categorized into three different groups according to their function and number of BH domains present in their structure: 1. anti-apoptotic members including Bcl-2, Bcl-xL and Mcl-1 that contain three or four BH domains, 2. pro-apoptotic members such as Bax and Bak that contain BH1, BH2 and BH3 and 3. pro-apoptotic BH3-only members including Bad, Bid, Noxa, Puma and BNIP3. The anti-apoptotic members can bind to BH3-only members through hydrophobic grooves formed by their BH domains. This interaction determines the activation status of this class of proteins. BH3-only members induce apoptosis by blocking the function of anti-apoptotic family members and/or by interacting with and activating pro-apoptotic proteins such as Bax and Bak. Anti-apoptotic Bcl-2 family proteins, block apoptosis by inhibiting the activity of pro-apoptotic proteins and preventing MOMP.

During apoptosis, anti-apoptotic protein levels decrease, while the levels of pro-apoptotic members rise; in fact, a decrease in the Bcl-2/Bax ratio is considered a reliable indicator of apoptosis. Furthermore, since the Bcl-2 family regulates mitochondrial permeability, their subcellular localization changes during apoptosis. For example, following apoptotic stimuli, Bax translocates from the cytosol to mitochondria. The extrinsic pathway can also induce mitochondrial apoptotic pathways since caspase-8 can cleave Bid (a Bcl-2 pro-apoptotic protein) to its active form namely tBid which promotes MOMP.

Caspases -3, -6 and -7 are considered “effector” caspases and cleave cellular products during the later stages of apoptosis. Caspase-9 and -8 can cleave caspase-3, while caspase-7 is a downstream target of caspase-9. Caspase-3 can also activate caspase-6. Active effector caspases break down many substrates ultimately causing DNA cleavage as well as nuclear and cytoskeletal protein degradation. The endonuclease Caspase-Activated DNase (CAD) is physiologically bound to ICAD (Inhibitor of Caspase-Activated DNase), a substrate of caspase-3. Upon its activation, CAD fragments DNA at ~180-bp pieces. PARP-1 is another caspase substate; normally, it participates in DNA repair mechanisms, but it is also involved in DNA replication and transcription, cellular repair, cytoskeletal organization and protein degradation. PARP-1 breakdown by caspases is crucial during apoptosis. The degradation of these targets ultimately leads to the biochemical and morphological changes observed in apoptotic cells including cell shrinkage, cytoplasmic condensation and generation of apoptotic bodies. At the final phase of apoptosis, phagocytic cell receptors recognize ligands presented on the surface of apoptotic bodies causing their destruction by professional phagocytic cells. The deregulation of apoptotic pathways that ultimately leads to MDR is described below.

3. Deregulation of the Intrinsic Apoptotic Pathway in MDR Tumors

A particularly important mechanism which promotes cancer cell resistance to chemotherapy is inhibition of apoptosis. Proteins involved in the intrinsic pathway of apoptosis, including Bcl-2 family members and the tumor-suppressor p53, are commonly deregulated in MDR cancers, whereas IAPs, which control caspase activation, are often overexpressed. In addition, related survival pathways, such as PI3K/AKT, often contribute to the development of resistance.

3.1. Bcl-2 Family Deregulation in MDR

Several proteins involved in the intrinsic pathway of apoptosis have been identified as important cellular oncogenes that not only promote tumorigenesis but also contribute to anti-cancer drug resistance. Inactivating mutations or deletions of pro-apoptotic Bax or Bak are rare, but many cancers, especially those being refractory to therapy, such as colon, gastric and leukemia, overexpress one or more pro-survival family members, including Bcl-2, Bcl-xL and Mcl-1. Initial studies in Bcl-2 transgenic mice revealed accumulation of lymphocytes resistant to diverse cytotoxic agents, including chemotherapeutic drugs. Multiple subsequent studies indicated that high levels of Bcl-2 gene expression correlate with severity of malignancy in cancer patients, including melanoma, breast, prostate, small cell lung, colorectal and bladder cancer, while increased Bcl-2 expression is associated with resistance to chemotherapy and radiation.

Another gene implicated in chemoresistance, is the tumor suppressor p53 which controls the transcription of numerous genes involved in DNA repair, metabolism, cell cycle arrest, apoptosis and senescence. One of the first physiological p53 functions described was its ability to induce apoptosis in transformed cells. p53 transcriptionally upregulates the expression of apoptotic-related proteins, such Puma, Noxa, Bid and Bax and can also physically interact with and neutralize the anti-apoptotic activity of Bcl-2 and Bcl-xL. Thus, p53 has a dual role both as a sensitizer, as well as an activator of apoptosis. p53 mutations, mainly missense mutations, repress apoptosis thus causing therapeutic resistance. Notably, mutant p53 can also inhibit apoptosis through the caspase-dependent apoptotic singling cascade. Overexpression of mutant p53 has been correlated with resistance to conventional drugs including cisplatin, antimetabolites (gemcitabine), anthracyclines, (doxorubicin), alkylating agents (temozolomide) and drugs with specific targets such as EGFR-inhibitors (cetuximab) and antiestrogens (tamoxifen). In addition to mutations in TP53 gene causing protein conformational changes, p53 activity may also be impaired due to alterations in p53-regulating proteins, such as MDM2. Therefore, several small molecules, that accelerate mutant p53 protein turnover or convert it into the wild-type conformation, have been developed and applied in clinical therapy. However, targeting p53 in tumor cells often leads to several side effects and drug cytotoxicity in normal tissues. Importantly, ROS regulate p53 activity by oxidizing the cysteine residues present in its structure. This modification leads to p53 inability to bind to DNA and activate specific genes.

3.2. Inhibitors of Apoptosis Proteins (IAPs) and Their Role in MDR

IAPs are a class of proteins that are frequently overexpressed in human cancers conveying resistance to apoptosis and therapy. IAP family members include Survivin, X-linked inhibitor of apoptosis (XIAP), inhibitors of apoptosis 1 and 2 (c-IAP1 and c-IAP2), BIR-repeat-containing ubiquitin-conjugating enzyme (BRUCE/Apollon), neuronal apoptosis inhibitor protein (NAIP), IAP-like protein 2 (ILP-2) and melanoma IAP (ML-IAP/Livin). IAPs contain one or more baculovirus inhibitor repeat (BIR) domains, an amino-terminal, 70-residue structure with distinct functions. In XIAP, the region between BIR1 and BIR2 specifically targets caspases -3 and -7 while BIR3 inhibits the activity of caspase-9. The RING domain, located in XIAP, Livin, ILP2, c-IAP-1 and c-IAP-2 protein structures, catalyzes the ubiquitination and proteasomal degradation of target proteins. c-IAP and c-IAP-2 are critical regulators of the noncanonical NFkB pathway and promote malignancy by inducing the degradation of NFkB-inducing kinase (NIK).

IAPs were originally thought to physically bind and block caspase activity, inhibiting both the extrinsic and intrinsic pathway of apoptosis. Some family members, including c-IAP1 and c-IAP2, have a caspase recruitment domain in their structure. However, with the notable exception of XIAP, they cannot directly bind and inhibit caspases. Under physiological conditions, IAP activity is controlled by Smac/DIABLO and Omi/HtrA2 that are released by the mitochondria and diminish their caspase-inhibitory effects. Overexpression of IAPs has been reported in many human cancers and has been correlated with resistance to therapy and worsening disease. High levels of c-IAP1, c-IAP2, XIAP, Survivin and NAIP have been reported in breast cancer. Furthermore, during early stages of pancreatic cancer, elevated levels of c-IAP2 contribute to malignant progression. In esophageal cancer, increased XIAP levels inhibit caspase-3 activation and lead to apoptosis resistance. Targeting IAP family members with agents that act as “SMAC mimetics” is widely investigated as a promising anti-cancer approach against MDR cancers.

Survivin is the smallest IAP protein. It is physiologically expressed during embryonic development to inhibit apoptosis and promote proliferation in developing tissues. Survivin is expressed at very low levels in differentiated tissues. However, it is overexpressed in most primary tumors and has been correlated with resistance to chemotherapy and radiotherapy-induced cell death as well as poor prognosis. Increased Survivin expression in cancer cells is partially attributed to aberrant activation of upstream survival pathways, such as NFkB, which transcriptionally upregulate Survivin. The anti-apoptotic mechanism of Survivin involves formation of a complex with XIAP, that protects XIAP from ubiquitin-dependent degradation and increases its caspase-inhibiting function. Furthermore, Survivin may sequester Smac/DIABLO away from XIAP or inhibit Smac/DIABLO translocation from the mitochondria to prevent XIAP inactivation. Therapeutic exploitation of Survivin is pivotal, as it represents a cancer cell-specific drug target. However, Survivin-targeting agents have performed poorly in clinical studies, highlighting the need for developing novel approaches against this protein.

3.3. PI3K/AKT Pathway in Multi-Drug Resistance

The synergy between apoptosis resistance and increased survival signaling is critically important in cancer development. The PI3K/AKT pathway responds to a variety of external signals and is involved in the regulation of different cellular functions, including cell cycle progression, survival, metabolism, gene transcription and maintenance of DNA integrity. Deregulation of this pathway has been implicated in MDR of many cancers, including leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, lung cancer and melanoma.

Binding of growth factors to receptor tyrosine kinases (RTKs) stimulate PI3K by autophosphorylation which leads to the phosphorylation and activation of serine/threonine kinase AKT (Protein Kinase B, PKB). RTK-PI3K complexes localize at the cell membrane where the PI3K subunit, p110, catalyzes the conversion of Phosphatidylinositol 4,5-bisphosphate PtdIns(4,5)P2 (PIP2) to Phosphatidylinositol (3,4,5)-triphosphate PtdIns(3,4,5)P3 (PIP3). Subsequently, AKT travels to the plasma membrane where it becomes phosphorylated. The tumor suppressor phosphatase and tensin homology deleted on chromosome 10 (PTEN) indirectly hinders AKT activity by converting PIP3 to PIP2. The phosphorylation of PTEN preserves its stability. Phosphoinositide-dependent kinase-1 and -2 (PDK1 and PDK2) are responsible for activating AKT via phosphorylation on residues Thr308 and Ser473, respectively. Phosphorylation of Thr308 partially activates AKT, while phosphorylation of both sites is required for its full activation. Once activated, p-AKT translocates to the cytosol or the nucleus where it phosphorylates and therefore modulates the function of downstream substrates, including several targets being implicated in cancer initiation and progression. AKT enhances cell survival by negatively regulating the function or expression of pro-apoptotic proteins that inactivate Bcl-2 family members. Additionally, AKT promotes survival by eliciting p53 degradation.

A large percentage of tumors carry alterations in PI3K, AKT or PTEN leading to MDR. The sustained expression of pro-survival signals renders cancer cells resistant to anticancer agents. Phosphorylated AKT enhances cell survival by phosphorylating many proteins implicated in apoptotic pathways, including glycogen synthase kinase-3 (GSK-3), forkhead transcription factors (FOXO), caspases and proteins implicated in NFkB signaling. AKT activates anti-apoptotic members of the Bcl-2 family, such as Bcl-2 and Bcl-xL, and IAPs including Survivin and XIAP via phosphorylation of the transcription factor cyclic AMP response element-binding protein (CREB) and IkB kinase (IKK), a positive regulator of NFkB. Increased activity of the PI3K/AKT pathway attenuates chemotherapy-induced apoptosis by diminishing the levels of pro-apoptotic Bax and increasing the levels of anti-apoptotic Bcl-2 and XIAP. In addition, AKT phosphorylates the pro-apoptotic protein Bad at Ser136, thus hindering its interaction with Bcl-xL and allowing the anti-apoptotic function of the latter. GSK-3, in response to insulin, regulates glycogen synthesis which has been shown to regulate cyclin D1 proteolysis and subcellular localization. GSK-3 activity is inhibited by AKT-mediated phosphorylation Ser21. AKT also activates the MEK-MAP kinase pathway in cancer cells promoting survival and proliferation, by phosphorylating cRAF at multiple amino acid residues, controlling its activity.. Importantly, AKT can directly inhibit the caspase cascade; pro-caspase-9 is an AKT substrate and can be phosphorylated on Ser196. Moreover, the phosphorylation of FOXO transcription factors by AKT causes their degradation in the cytoplasm and enhances cell survival by blocking the transcription of death receptor ligands TRAIL and Fas, and of pro-apoptotic Bcl-2 members Bim and BNIP3. The implication of FOXOs in the development of MDR is highlighted by their key role in regulating drug efflux pump ABCD1 in leukemic and breast cancers and by eliciting resistance to agents that act via the accumulation of ROS. A deeper understanding of the role of FOXOs in these two processes will enable the development of effective therapeutics.

Often, upstream and downstream proteins should also be deregulated to achieve MDR in cancer cells. Upstream regulators of PI3K, RTKs HER-2 and EGFR were found to be amplified in human cancers. HER-2 is overexpressed in 20–30% of primary breast cancers that also exhibit constitutive AKT activity, while EGFR overexpression has been reported in breast, lung and colorectal carcinoma and glioblastoma. Notably, almost 70% of endometrial and ovarian cancers harbor activating mutations of PIK3CA, the gene that encodes the p110α catalytic subunit of PI3K. PIK3CA mutation has been associated with elevated PI3K and AKT activity. A mutated form of the PIK3CA protein was also found to selectively phosphorylate AKT and FOXO promoting cellular growth and cancer cell invasion. The AKT2 gene is often amplified in human cancers, including lung and ovarian cancers while both AKT1 and AKT2 gene amplification has been reported in breast and colorectal cancers. As previously mentioned, PTEN is responsible for the indirect inactivation of AKT by converting PIP3 to PIP2, thus acting as a tumor suppressor. Loss of PTEN can occur either via gene mutation, deletion or promoter hypermethylation leading to elevated concentrations of the PIP3 substrate. Consequently, downstream components of the PI3K pathway, including AKT and mTOR, are constitutively active. Based on its implication in cancer cell progression, the PI3K/AKT pathway has been extensively studied as a promising drug target against malignant progression.

4. Implications of the TME in Apoptosis and MDR

The TME plays a crucial role in tumor growth, metastasis and development of MDR. The TME consists of immune cells, fibroblasts and endothelial cells that communicate with cancer cells through paracrine signaling. Immune cells present in the TME can activate or inhibit apoptotic pathways and affect response to therapy. Cytotoxic lymphocytes induce the activation of effector mechanisms, such as release of death ligands such as FasL and TRAIL, as well as activation of granule exocytosis pathway. Neutrophils and monocytes express TRAIL and target TRAIL receptor-expressing tumor cells. Macrophages, the major phagocytic cells of the innate immune system, can also induce TRAIL-mediated apoptosis of cancer cells. Cytokines, such IFNs, CD137 and IL-24, secreted by tumor-associated immune cells promote apoptosis in cancer cells. In addition, non-cellular TME constituents are important mediators of cancer cell behavior, such as excess extracellular matrix (ECM) deposition, which compresses blood vessels and reduces perfusion, as well as acidic and hypoxic milieu, which collectively impair drug delivery. Here, we mainly focus on the cellular components of the TME that regulate apoptosis of cancer cells and, more specifically, cancer associated fibroblasts (CAFs) which alter the apoptotic responses of cancer cells to cytotoxic drugs (Figure 2).

4.1. Cancer Associated Fibroblasts in Apoptosis and MDR

During carcinogenesis, CAFs are activated as a major component of the tumor stroma. CAFs secrete various extracellular matrix proteins, chemokines, cytokines, as well as growth factors and extensively contribute to tumor progression, invasion and metastasis. CAFs are also linked to poor survival in most cancers and are considered potential therapeutic targets. Factors released by CAFs increase tumor cell survival via the activation of anti-apoptotic pathways or by induction of the epithelial to mesenchymal transition (EMT) and cancer stem cell (CSC) phenotype, as demonstrated in melanoma, non-small cell lung cancer (NSCLC) and colorectal cancer.

4.1.1. CAF-Derived Extracellular Vesicles

The significance of extracellular vesicles (EVs) derived from CAFs (CAF-EVs) in the progression of carcinomas and resistance to apoptosis has been increasingly recognized. CAFs secrete exosomes that are loaded with proteins, lipids and RNAs to functionally control the properties of the TME. CAF-EVs exert tumor-promoting functions and microRNAs (miRNAs) found in CAF-EVs participate in the interaction between cancer cells and CAFs. Apoptosis of breast cancer cells is inhibited by CAF-EVs that reduce miR-30e expression to upregulate collagen triple helix repeat containing 1 (CTHRC1); this, in turn, activates the Wnt/β-catenin pathway to facilitate breast cancer development and progression. Overexpression of miR-30e or silencing of CTHRC1 suppresses proliferation, migration/invasion of breast cancer cells and promotes apoptosis. CAF-derived exosomes could also transfer miR-181d-5p to enhance breast cancer aggressiveness. CAFs antagonize apoptosis in MCF-7 cells via transfer of miR-181d-5p which downregulates homeobox A5 (HOXA5) and caudal-related homeobox 2 (CDX2). Long non-coding RNAs (lncRNAs) are a heterogeneous class of transcripts longer than 200 nucleotides with limited protein-coding potential. CAFs were shown to transfer lncRNA H19 to neighboring colorectal cancer cells and promote the stemness via activating Wnt/β-catenin signaling causing resistance to oxaliplatin-mediated apoptosis. Exosomal lncRNA enhance invasion, migration, proliferation and inhibit apoptosis in cervical cancer cells and in NSCLC. The importance of lncRNAs in regulating drug resistance in cancer cells has recently been described in a detailed review.

4.1.2. Interleukins Secreted by CAFs

Lung adenocarcinoma is one of the most CAF-rich cancers. The role of CAFs in resistance to chemotherapy of lung adenocarcinoma is well appreciated. Cisplatin treatment increases Interleukin-11 (IL-11) levels in CAFs which protects lung adenocarcinoma cells from apoptosis. Cisplatin induces DNA damage and subsequently activation of apoptosis. IL-11, a member of IL-6 family, binds to IL-11Ra2 to activate signaling.. Patients with high IL-11Rα levels show poor response to cisplatin-based chemotherapy. IL-11 induces Signal transducer and activator of transcription 3 (STAT3) phosphorylation and increases the expression of anti-apoptotic protein Bcl-2 and Survivin in cancer cells. As mentioned above, Bcl-2 and Survivin have been extensively implicated in the development of chemoresistance in cancer. The anti-apoptotic effects of IL-11 can be prevented by suppressing STAT3 phosphorylation or silencing IL-11Rα expression in lung adenocarcinoma.

IL-6 is another key cytokine, secreted by cancer cells, immune cells and CAFs, which inhibits apoptosis of cancer cells through STAT3 activation. IL-6 binds to the cell surface receptor glycoprotein 130 (gp130) and activates several cell survival-related pathways promoting chemotherapeutic resistance in breast, ovarian and endometrial cancers. Significant amount of IL-6 in the TME originates from CAFs and is involved in carcinogenesis and metastasis. IL-6 derived from CAFs prevents chemotherapy-induced apoptosis by increasing the phosphorylation of Jak1 and STAT3, and the expression of the anti-apoptotic proteins Bcl-2 and Survivin in gastric carcinoma. Studies conducted in CAFs derived from human gastric carcinomas further demonstrated the role of CAFs in prevention of early apoptosis of gastric cancer cells treated with 5-fluorouracil (5-FU). Factors secreted from CAFs not only inhibit apoptosis but also induce an EMT phenotype in gastric carcinoma. Treatment with conditioned medium from activated gastric carcinoma CAFs decreases response of gastric cancer cells to 5-FU by suppression of apoptosis-related proteins, such as Bak, Bax, cleaved caspase 3 and cleaved PARP. Similarly, chemotherapy-induced apoptosis of pancreatic cancer cells significantly decreases in the presence of CAFs. Overall, the role of IL-6, IL-11 as well as of other interleukins, has been observed in MDR cancer cells; the clinical attempts to block their effects for therapeutic intervention have been described in a recent review.

4.1.3. Regulation of Sex Determining Region Y-box 2 by CAFs

Sex determining region Y -box 2 (Sox2), an essential embryonal stem cell transcription factor, may also play an important role in CAF-induced drug resistance. Sox2 is linked to the formation and maintenance of CSC phenotype and is implicated in drug resistance and poor patient prognosis. In ER+ breast cancer cells, a mixture of CAF-secreted factors strongly induced Sox2 expression. In addition, Sox2 blocked apoptosis, enabled cellular growth and shielded cells against the anti-estrogen fulvestrant. CAFs also minimized the effectiveness of tamoxifen in breast cancer cells. Whereas Sox2 is an attractive therapeutic target, direct targeting of Sox2 via siRNA has shown poor outcomes due to inefficient delivery and efficacy; novel approaches include the design of artificial transcription factors (ATFs), that bind to proximal SOX2 promoters and reduce its expression.

4.1.4. Growth Promoting Proteins Released by CAFs

CAFs secrete hepatocyte growth factor (HGF) that mediates resistance to cancer cell apoptosis. HGF also induces cell proliferation, cancer cell motility and migration. Many cancer types, including ovarian, gastric, colorectal and pancreatic, overexpress c-Met, which functions as a specific HGF receptor. HGF-induced c-Met activation triggers downstream the PI3K/Akt pathway, enabling cancer progression. In lung cancer, HGF derived from CAFs, attenuates the apoptotic effects of paclitaxel (PAC) by upregulating glucose-regulated protein 78 (GRP78). GRP78 acts as a chaperon protein in the endoplasmic reticulum (ER) where it regulates protein folding; it is highly expressed on the surface of cancer cells and enables malignant growth, motility, migration and resistance to therapy. In ovarian cancer, HGF secreted by CAFs attenuated paclitaxel-induced apoptosis by activating the c-Met/PI3K/Akt pathway and signaling involving GRP78. In addition, GRP78 inhibits apoptosis by interacting with caspase-7 or p53 and also by binding to Bax and Bik to prevent mitochondrial release of cyt-c. This evidence suggests that the activation of PI3K/Akt and GRP78 may be implicated in cancer progression and resistance to therapy. Activation of PI3K/Akt pathway by other CAF-originated factors can also lead to resistance to apoptosis induced by cytotoxic drugs. More specifically, the CAF-derived chemokine CCL5, promoted cisplatin resistance in ovarian cancer cells by affecting the PI3K/Akt signaling pathway. Netrin-1 is a multifunctional secreted glycoprotein upregulated in various cancers, such as gastric and lung, and may inhibit apoptosis induced by the dependence receptors DCC and UNC5H. Netrin-1 and its receptor (UNC5B) are upregulated in CAFs of lung and colon tumors. Inhibition of netrin-1 abrogates CAF-mediated increase in cancer stemness. Hence, Netrin-1 secreted by CAFs may play an important role in inhibition of apoptosis and drug resistance.

TP53-regulated inhibitor of apoptosis 1 (TRIAP1) is a small, 76-amino acid long, evolutionary conserved protein which inhibits apoptosis and promotes DNA repair. Loss of caveolin-1 in CAFs augmented the secretion of TRIAP1 from CAFs causing radiation resistance of prostate cancer cells by hindering apoptosis. Similarly, knockdown of TRIAP1, using microRNA miR-320b, induced mitochondrial apoptosis.

Folicular lymphoma-associated CAFs, isolated from malignant lymphoma patients, were shown to protect tumor cells from apoptosis in response to cytotoxic drugs. These CAFs do not alter proliferation rate of cancer cells but markedly upregulate the expression of the anti-apoptotic BCL2L1 gene in folicular lymphoma cells. Midkine can also mediate CAF-induced inhibition of apoptosis and chemoresistance. Midkine is a heparin-binding growth factor and induces tumor progression by enhancing carcinoma cell growth, survival, invasiveness, migration, and chemotherapy resistance. Primary CAFs from oral squamous cell carcinoma secrete high levels of midkine, which abrogate cisplatin-induced cell death. Midkine also enables glioma cells to become resistant to tetrahydrocannabinol by obstructing the ALK receptor and inhibiting autophagy-mediated cell death via the Akt/mTORC1 pathway. Midkine induces the expression of lncRNA ANRIL in cancer cells while lncRNA ANRIL knockdown blocked proliferation and promoted apoptosis to augment cisplatin cytotoxicity via impairment of the drug transporters MRP1 and ABCC2. Furthermore, knockdown of lncRNA ANRIL increased the activation of caspase-3 and inhibited Bcl-2 expression.

Conclusively, CAFs not only enhance the aggressiveness of cancer cells but also render them resistant to therapy-induced apoptotic effects by secreting various factors including miRNAs, lncRNAs, cytokines and chemokines. All these CAF-secreted factors induce activation or upregulation of factors implicated in apoptosis inhibition and overactivation of survival pathways in cancer cells in response to chemotherapy. Given the crucial roles of CAFs in carcinogenesis and drug resistance, better understanding of the underlying mechanisms will uncover novel targets to overcome drug resistance mediated via deregulation of cell death pathways.

5. Therapeutic Approaches to Induce Apoptosis in MDR Cancers

Potent apoptosis-inducing approaches can prevent tumor initiation and progression. Many proteins involved in apoptosis have been targeted with small molecule inhibitors, epigenetic drugs and natural or synthetic compounds (Table 1). These agents may be used as monotherapy, but they have been often evaluated in combination with other targeted or conventional anti-tumor therapeutics. The Bcl-2 family of proteins represent an attractive target for therapy as it is often deregulated and confers resistance in cancer. Consequently, small molecule inhibitors that can interact with BH3 domains and antisense oligonucleotides have been developed. These small molecules against Bcl-2 proteins can be categorized as BH3 mimetics (i.e., ABT-737, ABT-263) and small molecules with BH3 putative mimetic action (i.e., gossypol, obatoclax etc.).

Inhibiting AKT has for long been a major focus as a promising therapeutic approach in cancer. To date, there are two classes of AKT inhibitors, namely, ATP-competitive and allosteric inhibitors which either block ATP binding or prevent AKT phosphorylation and activation. However, despite the development of many compounds with promising results for targeting AKT, none of these inhibitors has been approved yet for clinical use. This is, at least in part, attributed to the complex and pleiotropic functions that AKT exerts in cells. Therefore, combinational therapy approaches seem to represent a major research direction for the successful clinical utilization of AKT inhibitors.

Conventional drugs, such as cisplatin and doxorubicin, exert their anti-cancer effects via the accumulation of ROS and DNA damage. However, reduction of ROS generation leads to resistance. Moreover, synthetic agents tested against MDR cancers, can sometimes cause toxic side effects and lack specificity. For these reasons, efforts have also been focused on natural agents and their derivatives, to take advantage of their beneficial properties. Polyphenols represent a large family of organic, naturally occurring compounds that are characterized by the presence of many phenol groups in their structure. Phenolic compounds, including flavones, ellagitannins and curcumin, are known to act as chemopreventive agents due to their antioxidant properties and their ability to inactivate pro-carcinogens. Certain natural compounds, rely on the upregulation of ROS to induce DNA damage. However, low oxygen levels within the tumor leads to limited generation of ROS and allows cancer cells to escape death. Reduced ROS levels in cancer cells have been reported to increase the levels of P-gp efflux pump through the JNK pathway, further promoting drug resistance. Importantly, natural compounds also exert chemotherapeutic properties because they can regulate signaling pathways to inhibit the proliferation of cancer cells, block angiogenesis and metastasis, and induce immune and inflammatory responses. Importantly, phenolic compounds can induce apoptosis in cancer cells by activating various pro-apoptotic machineries and, interestingly, several have been reported to be effective against MDR tumors. The TME is also being targeted to improve drug efficacy in difficult to treat cancers; immune checkpoint inhibitors (ICIs) that have shown promising clinical efficacy, are now being tested in combination with other agents to overcome intrinsic or acquired tumor resistance.

6. Future Perspectives: The Implication and Therapeutic Exploitation of Epigenetics in MDR

For decades, genetic mutations during cancer progression and acquired MDR were considered a major cause of treatment failure in relapsed cases, ignoring the non-genetic basis of tumor heterogeneity. A breakthrough in anti-cancer therapy was achieved when it was realized that the high predominance of MDR is attributed not only to DNA mutations but also to a variety of epigenetic alterations. Moreover, it became increasingly evident that the probability of an irreversible mutation to appear, increases as more critical modifications emerge in the epigenome of tumor cells. Among the observations that led to this conclusion were the reversal of drug resistance observed upon drug-free periods, the frequent absence of mutations in drug targets or activated pathways, as well as the heterogeneity in acquired MDR and in relapsed cases. Recent data highlight the major role of epigenetic changes in tumorigenesis and in the development of MDR. Cancer cells can escape from a poised drug-tolerant condition and enter into an epigenetically fixed acquired-resistant state via poorly understood mechanisms. During carcinogenesis, environmental pressure upon tumor cells results in an array of epigenetic aberrations, such as DNA and RNA methylation, alterations in the miRNAs expression and histone modifications, which eventually lead to epigenetically-induced transcriptional adaptation.

Epigenetic changes are generally reversible and susceptible to external factors; these characteristics make them appealing targets either for monotherapy or in combination with other anti-cancer agents to treat MDR. Therefore, multiple generations of drugs that target epigenetic regulators, called epi-drugs, have been designed during the last 40 years, demonstrating valuable effects on cancer therapy in clinical trials. Epigenetic modifications such as DNA hypermethylation of gene promoters could partially explain the acquired resistance after prolonged treatment. Recent studies have shown that epi-drugs, such as the DNA methylation inhibitor (iDNMT), 5-aza-20-deoxycytidine (decitabine; DAC), can be effective against resistant cancers (including lung cancer and AML), in combination with conventional chemotherapeutics by reversing DNA methylation which sensitizes cancer cells to other chemotherapeutics, including carboplatin, cisplatin and 5-FU.

Several challenges remain, however, to improve the effectiveness of epi-drugs against MDR cancers. In contrast to hematological malignancies, solid tumors do not respond well to epi-drugs possibly due to the contribution of the TME. To overcome these obstacles, single-cell sequencing technologies (i.e., scRNA-seq, scATAC-seq, sc-Hi-C and scChIP-seq) using patients’ biopsies immediately before and/or after epi-drug administration could provide more detailed information about the drug resistance landscape derived from genome/epigenome interactions. In addition, many epi-drugs, such as HDACs inhibitors which were shown to be effective against hematological malignancies and MDR, result in numerous off-target effects, since they act as pan-HDAC inhibitors. A novel therapeutic approach, called proteolysis-targeting chimera (PROTAC) has been developed to improve the specificity of drugs against targets at low concentrations. The PROTACs technology promotes proteasomal protein degradation through E3 ubiquitin ligase activity. Importantly, side effects are significantly reduced. PROTAC drugs targeting the epigenetic reader BRD4 are under preclinical evaluation in various cancer types showing promising therapeutic effects in reversing drug resistance phenotypes. In addition, the replacement of preclinical models, such as two-dimensional (2D) in vitro cancer cell lines, with more clinically relevant 3D in vitro or mouse models that recapitulate the TME of resistant cells in relapsed patients should be considered. Importantly, epigenetic interpatient and intratumor heterogeneity, a hallmark of human cancers that plays crucial roles in developing MDR need to be more thoroughly investigated. Taken together, current evidence suggests that to improve efficacy of epi-drugs, new generations of more selective agents should be developed with optimized drug dosage, pharmacodynamics and pharmacokinetics properties, along with low toxicity levels in normal cells and tissues.

7. Conclusions

Deregulation of the major apoptotic pathways, and the related survival pathways that control the expression and/or activation of apoptotic proteins, may lead to MDR. Imbalance in Bcl-2 family levels, overexpression of IAPs and p53 inactivation have been widely reported in various types of MDR tumors. The TME appears to be pivotal in tumor progression and is known to impair the effectiveness of many therapeutics. A better understanding of how epigenetic alterations control cancer development may lead improved drug efficacy and contribute to the improvement of several agents already employed against MDR tumors. Recent studies using in vitro models have shown that different MDR mechanisms can be derived from a single ancestor cell. Subsequently, in these cases, detection and characterization of residual tumor cells using single-cell sequencing technologies, will elucidate the contribution of genetic and epigenetic variability in developing drug resistance phenotypes. It has been suggested that one of the better strategies in the fight against acquired MDR could be a therapeutic scheme that targets cancer cells prior to the acquisition of drug resistance, i.e., before they express a pro-survival program. At the dawn of personalized medicine, the study of these alterations could provide novel and promising predictive biomarkers with great clinical significance against the evolution of acquired MDR.

References 291

  1. 1.

    Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2020. CA Cancer J. Clin. 2020;70:7-30.

    Not in our library10.3322/caac.21590

  2. 2.

    Yersal O., Barutca S. Biological subtypes of breast cancer: Prognostic and therapeutic implications. World J. Clin. Oncol. 2014;5:412-424.

    Not in our library10.5306/wjco.v5.i3.412

  3. 3.

    Tsaur I., Heidegger I., Kretschmer A., Borgmann H., Gandaglia G., Briganti A., de Visschere P., Mathieu R., Valerio M., van den Bergh R., et al. Aggressive variants of prostate cancer—Are we ready to apply specific treatment right now? Cancer Treat. Rev. 2019;75:20-26.

    Not in our library10.1016/j.ctrv.2019.03.001

  4. 4.

    Nguyen K.S., Neal J.W., Wakelee H. Review of the current targeted therapies for non-small-cell lung cancer. World J. Clin. Oncol. 2014;5:576-587.

    Not in our library10.5306/wjco.v5.i4.576

  5. 5.

    Kozovska Z., Gabrisova V., Kucerova L. Colon cancer: Cancer stem cells markers, drug resistance and treatment. Biomed. Pharmacother. Biomed. Pharmacother. 2014;68:911-916.

    Not in our library10.1016/j.biopha.2014.10.019

  6. 6.

    Assaraf Y.G., Brozovic A., Goncalves A.C., Jurkovicova D., Line A., Machuqueiro M., Saponara S., Sarmento-Ribeiro A.B., Xavier C.P.R., Vasconcelos M.H. The multi-factorial nature of clinical multidrug resistance in cancer. Drug Resist. Updates Rev. Comment. Antimicrob. Anticancer Chemother. 2019;46:100645.

    Not in our library10.1016/j.drup.2019.100645

  7. 7.

    Hanahan D., Weinberg R.A. Hallmarks of cancer: The next generation. Cell. 2011;144:646-674.

    Not in our library10.1016/j.cell.2011.02.013

  8. 8.

    Plati J., Bucur O., Khosravi-Far R. Apoptotic cell signaling in cancer progression and therapy. Integr. Biol. 2011;3:279-296.

    Not in our library10.1039/c0ib00144a

  9. 9.

    Elmore S. Apoptosis: A review of programmed cell death. Toxicol. Pathol. 2007;35:495-516.

    Not in our library10.1080/01926230701320337

  10. 10.

    Savill J., Fadok V. Corpse clearance defines the meaning of cell death. Nature. 2000;407:784-788.

    Not in our library10.1038/35037722

  11. 11.

    Kurosaka K., Takahashi M., Watanabe N., Kobayashi Y. Silent cleanup of very early apoptotic cells by macrophages. J. Immunol. 2003;171:4672-4679.

    Not in our library10.4049/jimmunol.171.9.4672

  12. 12.

    Suliman A., Lam A., Datta R., Srivastava R.K. Intracellular mechanisms of TRAIL: Apoptosis through mitochondrial-dependent and -independent pathways. Oncogene. 2001;20:2122-2133.

    Not in our library10.1038/sj.onc.1204282

  13. 13.

    Ashkenazi A., Dixit V.M. Death receptors: Signaling and modulation. Science. 1998;281:1305-1308.

    Not in our library10.1126/science.281.5381.1305

  14. 14.

    Chicheportiche Y., Bourdon P.R., Xu H., Hsu Y.M., Scott H., Hession C., Garcia I., Browning J.L. TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis. J. Biol. Chem. 1997;272:32401-32410.

    Not in our library10.1074/jbc.272.51.32401

  15. 15.

    Peter M.E., Krammer P.H. Mechanisms of CD95 (APO-1/Fas)-mediated apoptosis. Curr. Opin. Immunol. 1998;10:545-551.

    Not in our library10.1016/s0952-7915(98)80222-7

  16. 16.

    Rubio-Moscardo F., Blesa D., Mestre C., Siebert R., Balasas T., Benito A., Rosenwald A., Climent J., Martinez J.I., Schilhabel M., et al. Characterization of 8p21.3 chromosomal deletions in B-cell lymphoma: TRAIL-R1 and TRAIL-R2 as candidate dosage-dependent tumor suppressor genes. Blood. 2005;106:3214-3222.

    Not in our library10.1182/blood-2005-05-2013

  17. 17.

    Guicciardi M.E., Gores G.J. Life and death by death receptors. FASEB J. 2009;23:1625-1637.

    Not in our library10.1096/fj.08-111005

  18. 18.

    Boldin M.P., Mett I.L., Varfolomeev E.E., Chumakov I., Shemer-Avni Y., Camonis J.H., Wallach D. Self-association of the “death domains” of the p55 tumor necrosis factor (TNF) receptor and Fas/APO1 prompts signaling for TNF and Fas/APO1 effects. J. Biol. Chem. 1995;270:387-391.

    Not in our library10.1074/jbc.270.1.387

  19. 19.

    Wajant H. The Fas signaling pathway: More than a paradigm. Science. 2002;296:1635-1636.

    Not in our library10.1126/science.1071553

  20. 20.

    Hsu H., Xiong J., Goeddel D.V. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell. 1995;81:495-504.

    Not in our library10.1016/0092-8674(95)90070-5

  21. 21.

    Jin Z., El-Deiry W.S. Overview of cell death signaling pathways. Cancer Biol. Ther. 2005;4:139-163.

    Not in our library10.4161/cbt.4.2.1508

  22. 22.

    Kischkel F.C., Hellbardt S., Behrmann I., Germer M., Pawlita M., Krammer P.H., Peter M.E. Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J. 1995;14:5579-5588.

    Not in our library10.1002/j.1460-2075.1995.tb00245.x

  23. 23.

    Li J., Yuan J. Caspases in apoptosis and beyond. Oncogene. 2008;27:6194-6206.

    Not in our library10.1038/onc.2008.297

  24. 24.

    Pop C., Salvesen G.S. Human caspases: Activation, specificity, and regulation. J. Biol. Chem. 2009;284:21777-21781.

    Not in our library10.1074/jbc.r800084200

  25. 25.

    Cohen G.M. Caspases: The executioners of apoptosis. Biochem. J. 1997;326:1-16.

    Not in our library10.1042/bj3260001

  26. 26.

    Degterev A., Boyce M., Yuan J. A decade of caspases. Oncogene. 2003;22:8543-8567.

    Not in our library10.1038/sj.onc.1207107

  27. 27.

    Saelens X., Festjens N., Vande Walle L., van Gurp M., van Loo G., Vandenabeele P. Toxic proteins released from mitochondria in cell death. Oncogene. 2004;23:2861-2874.

    Not in our library10.1038/sj.onc.1207523

  28. 28.

    Chinnaiyan A.M. The apoptosome: Heart and soul of the cell death machine. Neoplasia. 1999;1:5-15.

    Not in our library10.1038/sj.neo.7900003

  29. 29.

    Hill M.M., Adrain C., Duriez P.J., Creagh E.M., Martin S.J. Analysis of the composition, assembly kinetics and activity of native Apaf-1 apoptosomes. EMBO J. 2004;23:2134-2145.

    Not in our library10.1038/sj.emboj.7600210

  30. 30.

    Van Loo G., van Gurp M., Depuydt B., Srinivasula S.M., Rodriguez I., Alnemri E.S., Gevaert K., Vandekerckhove J., Declercq W., Vandenabeele P. The serine protease Omi/HtrA2 is released from mitochondria during apoptosis. Omi interacts with caspase-inhibitor XIAP and induces enhanced caspase activity. Cell Death Differ. 2002;9:20-26.

    Not in our library10.1038/sj.cdd.4400970

  31. 31.

    Schimmer A.D. Inhibitor of apoptosis proteins: Translating basic knowledge into clinical practice. Cancer Res. 2004;64:7183-7190.

    Not in our library10.1158/0008-5472.can-04-1918

  32. 32.

    Giam M., Huang D.C., Bouillet P. BH3-only proteins and their roles in programmed cell death. Oncogene. 2008;27(Suppl. S1):S128-136.

    Not in our library10.1038/onc.2009.50

  33. 33.

    Danial N.N. BCL-2 family proteins: Critical checkpoints of apoptotic cell death. Clin. Cancer Res. 2007;13:7254-7263.

    Not in our library10.1158/1078-0432.ccr-07-1598

  34. 34.

    Youle R.J., Strasser A. The BCL-2 protein family: Opposing activities that mediate cell death. Nat. Rev. Mol. Cell Biol. 2008;9:47-59.

    Not in our library10.1038/nrm2308

  35. 35.

    Hinds M.G., Day C.L. Regulation of apoptosis: Uncovering the binding determinants. Curr. Opin. Struct. Biol. 2005;15:690-699.

    Not in our library10.1016/j.sbi.2005.10.003

  36. 36.

    Ghiotto F., Fais F., Bruno S. BH3-only proteins: The death-puppeteer’s wires. Cytom. A. 2010;77:11-21.

    Not in our library10.1002/cyto.a.20819

  37. 37.

    Esposti M.D. The roles of Bid. Apoptosis. 2002;7:433-440.

    Not in our library10.1023/a:1020035124855

  38. 38.

    Igney F.H., Krammer P.H. Death and anti-death: Tumour resistance to apoptosis. Nat. Rev. Cancer. 2002;2:277-288.

    Not in our library10.1038/nrc776

  39. 39.

    Cullen S.P., Martin S.J. Caspase activation pathways: Some recent progress. Cell Death Differ. 2009;16:935-938.

    Not in our library10.1038/cdd.2009.59

  40. 40.

    Enari M., Sakahira H., Yokoyama H., Okawa K., Iwamatsu A., Nagata S. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature. 1998;391:43-50.

    Not in our library10.1038/34112

  41. 41.

    Hong S.J., Dawson T.M., Dawson V.L. Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling. Trends Pharm. Sci. 2004;25:259-264.

    Not in our library10.1016/j.tips.2004.03.005

  42. 42.

    Luthi A.U., Martin S.J. The CASBAH: A searchable database of caspase substrates. Cell Death Differ. 2007;14:641-650.

    Not in our library10.1038/sj.cdd.4402103

  43. 43.

    Khosravi-Far R., Esposti M.D. Death receptor signals to mitochondria. Cancer Biol. Ther. 2004;3:1051-1057.

    Not in our library10.4161/cbt.3.11.1173

  44. 44.
    Drug Resistance in Cancer: An Overview · 2014
    No notice
  45. 45.

    Campana D., Coustan-Smith E., Manabe A., Buschle M., Raimondi S.C., Behm F.G., Ashmun R., Arico M., Biondi A., Pui C.H. Prolonged survival of B-lineage acute lymphoblastic leukemia cells is accompanied by overexpression of bcl-2 protein. Blood. 1993;81:1025-1031.

    Not in our library10.1182/blood.v81.4.1025.1025

  46. 46.

    Mason K.D., Vandenberg C.J., Scott C.L., Wei A.H., Cory S., Huang D.C., Roberts A.W. In vivo efficacy of the Bcl-2 antagonist ABT-737 against aggressive Myc-driven lymphomas. Proc. Natl. Acad. Sci. USA. 2008;105:17961-17966.

    Not in our library10.1073/pnas.0809957105

  47. 47.

    Othman R.T., Kimishi I., Bradshaw T.D., Storer L.C., Korshunov A., Pfister S.M., Grundy R.G., Kerr I.D., Coyle B. Overcoming multiple drug resistance mechanisms in medulloblastoma. Acta Neuropathol. Commun. 2014;2:57.

    Not in our library10.1186/2051-5960-2-57

  48. 48.

    Beroukhim R., Mermel C.H., Porter D., Wei G., Raychaudhuri S., Donovan J., Barretina J., Boehm J.S., Dobson J., Urashima M., et al. The landscape of somatic copy-number alteration across human cancers. Nature. 2010;463:899-905.

    Not in our library10.1038/nature08822

  49. 49.

    Cory S., Roberts A.W., Colman P.M., Adams J.M. Targeting BCL-2-like Proteins to Kill Cancer Cells. Trends Cancer. 2016;2:443-460.

    Not in our library10.1016/j.trecan.2016.07.001

  50. 50.

    McDonnell T.J., Deane N., Platt F.M., Nunez G., Jaeger U., McKearn J.P., Korsmeyer S.J. bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell. 1989;57:79-88.

    Not in our library10.1016/0092-8674(89)90174-8

  51. 51.

    Strasser A., Whittingham S., Vaux D.L., Bath M.L., Adams J.M., Cory S., Harris A.W. Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. Proc. Natl. Acad. Sci. USA. 1991;88:8661-8665.

    Not in our library10.1073/pnas.88.19.8661

  52. 52.

    Sentman C.L., Shutter J.R., Hockenbery D., Kanagawa O., Korsmeyer S.J. bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell. 1991;67:879-888.

    Not in our library10.1016/0092-8674(91)90361-2

  53. 53.

    Thomas S., Quinn B.A., Das S.K., Dash R., Emdad L., Dasgupta S., Wang X.Y., Dent P., Reed J.C., Pellecchia M., et al. Targeting the Bcl-2 family for cancer therapy. Expert Opin. Ther. Targets. 2013;17:61-75.

    Not in our library10.1517/14728222.2013.733001

  54. 54.

    Khoo K.H., Verma C.S., Lane D.P. Drugging the p53 pathway: Understanding the route to clinical efficacy. Nat. Rev. Drug Discov. 2014;13:217-236.

    Not in our library10.1038/nrd4236

  55. 55.

    Kruiswijk F., Labuschagne C.F., Vousden K.H. p53 in survival, death and metabolic health: A lifeguard with a licence to kill. Nat. Rev. Mol. Cell Biol. 2015;16:393-405.

    Not in our library10.1038/nrm4007

  56. 56.

    Green D.R., Kroemer G. Cytoplasmic functions of the tumour suppressor p53. Nature. 2009;458:1127-1130.

    Not in our library10.1038/nature07986

  57. 57.
    The PROTAC technology in drug development · 2019
    No notice
  58. 58.

    Marino G., Niso-Santano M., Baehrecke E.H., Kroemer G. Self-consumption: The interplay of autophagy and apoptosis. Nat. Rev. Mol. Cell Biol. 2014;15:81-94.

    Not in our library10.1038/nrm3735

  59. 59.
    The role of p53 in cancer drug resistance and targeted chemotherapy · 2016
    No notice
  60. 60.
    Inhibition of p53 inhibitors: progress, challenges and perspectives · 2019
    No notice
  61. 61.

    Liu B., Chen Y., St Clair D.K. ROS and p53: A versatile partnership. Free Radic. Biol. Med. 2008;44:1529-1535.

    Not in our library10.1016/j.freeradbiomed.2008.01.011

  62. 62.

    Mita A.C., Mita M.M., Nawrocki S.T., Giles F.J. Survivin: Key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin. Cancer Res. 2008;14:5000-5005.

    Not in our library10.1158/1078-0432.ccr-08-0746

  63. 63.

    Vaux D.L., Silke J. IAPs, RINGs and ubiquitylation. Nat. Rev. Mol. Cell Biol. 2005;6:287-297.

    Not in our library10.1038/nrm1621

  64. 64.

    Varfolomeev E., Blankenship J.W., Wayson S.M., Fedorova A.V., Kayagaki N., Garg P., Zobel K., Dynek J.N., Elliott L.O., Wallweber H.J., et al. IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell. 2007;131:669-681.

    Not in our library10.1016/j.cell.2007.10.030

  65. 65.

    Salvesen G.S., Duckett C.S. IAP proteins: Blocking the road to death’s door. Nat. Rev. Mol. Cell Biol. 2002;3:401-410.

    Not in our library10.1038/nrm830

  66. 66.

    Eckelman B.P., Salvesen G.S., Scott F.L. Human inhibitor of apoptosis proteins: Why XIAP is the black sheep of the family. EMBO Rep. 2006;7:988-994.

    Not in our library10.1038/sj.embor.7400795

  67. 67.

    LaCasse E.C., Mahoney D.J., Cheung H.H., Plenchette S., Baird S., Korneluk R.G. IAP-targeted therapies for cancer. Oncogene. 2008;27:6252-6275.

    Not in our library10.1038/onc.2008.302

  68. 68.

    Hunter A.M., LaCasse E.C., Korneluk R.G. The inhibitors of apoptosis (IAPs) as cancer targets. Apoptosis. 2007;12:1543-1568.

    Not in our library10.1007/s10495-007-0087-3

  69. 69.

    Peng X.H., Karna P., O’Regan R.M., Liu X., Naithani R., Moriarty R.M., Wood W.C., Lee H.Y., Yang L. Down-regulation of inhibitor of apoptosis proteins by deguelin selectively induces apoptosis in breast cancer cells. Mol. Pharm. 2007;71:101-111.

    Not in our library10.1124/mol.106.027367

  70. 70.

    Esposito I., Kleeff J., Abiatari I., Shi X., Giese N., Bergmann F., Roth W., Friess H., Schirmacher P. Overexpression of cellular inhibitor of apoptosis protein 2 is an early event in the progression of pancreatic cancer. J. Clin. Pathol. 2007;60:885-895.

    Not in our library10.1136/jcp.2006.038257

  71. 71.

    Zhang S., Ding F., Luo A., Chen A., Yu Z., Ren S., Liu Z., Zhang L. XIAP is highly expressed in esophageal cancer and its downregulation by RNAi sensitizes esophageal carcinoma cell lines to chemotherapeutics. Cancer Biol. Ther. 2007;6:973-980.

    Not in our library10.4161/cbt.6.6.4195

  72. 72.
    Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs) · 2017
    No notice
  73. 73.

    Shiozaki A., Kataoka K., Fujimura M., Yuki H., Sakai M., Saito S. Survivin inhibits apoptosis in cytotrophoblasts. Placenta. 2003;24:65-76.

    Not in our library10.1053/plac.2002.0860

  74. 74.

    Lehner R., Bobak J., Kim N.W., Shroyer A.L., Shroyer K.R. Localization of telomerase hTERT protein and survivin in placenta: Relation to placental development and hydatidiform mole. Obstet. Gynecol. 2001;97:965-970.

    Not in our library10.1097/00006250-200106000-00018

  75. 75.

    O’Connor D.S., Grossman D., Plescia J., Li F., Zhang H., Villa A., Tognin S., Marchisio P.C., Altieri D.C. Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin. Proc. Natl. Acad. Sci. USA. 2000;97:13103-13107.

    Not in our library10.1073/pnas.240390697

  76. 76.

    Altieri D.C. Survivin and IAP proteins in cell-death mechanisms. Biochem. J. 2010;430:199-205.

    Not in our library10.1042/bj20100814

  77. 77.

    Waligorska-Stachura J., Jankowska A., Wasko R., Liebert W., Biczysko M., Czarnywojtek A., Baszko-Blaszyk D., Shimek V., Ruchala M. Survivin--prognostic tumor biomarker in human neoplasms—Review. Ginekol. Pol. 2012;83:537-540.

    Not in our library

  78. 78.

    Xu C., Yamamoto-Ibusuki M., Yamamoto Y., Yamamoto S., Fujiwara S., Murakami K., Okumura Y., Yamaguchi L., Fujiki Y., Iwase H. High survivin mRNA expression is a predictor of poor prognosis in breast cancer: A comparative study at the mRNA and protein level. Breast Cancer. 2012.

    Not in our library10.1007/s12282-012-0403-9

  79. 79.
    Impacting tumor cell-fate by targeting the inhibitor of apoptosis protein survivin · 2011
    No notice
  80. 80.

    Neophytou C.M., Constantinou A.C. C. Survivin: Transcriptional Regulation and Protein Function in Cancer. J. Immunol. 2017.

    Not in our library

  81. 81.

    Richmond A. Nf-kappa B, chemokine gene transcription and tumour growth. Nat. Rev. Immunol. 2002;2:664-674.

    Not in our library10.1038/nri887

  82. 82.

    Dohi T., Okada K., Xia F., Wilford C.E., Samuel T., Welsh K., Marusawa H., Zou H., Armstrong R., Matsuzawa S., et al. An IAP-IAP complex inhibits apoptosis. J. Biol. Chem. 2004;279:34087-34090.

    Not in our library10.1074/jbc.c400236200

  83. 83.

    Song Z., Yao X., Wu M. Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis. J. Biol. Chem. 2003;278:23130-23140.

    Not in our library10.1074/jbc.m300957200

  84. 84.

    Ceballos-Cancino G., Espinosa M., Maldonado V., Melendez-Zajgla J. Regulation of mitochondrial Smac/DIABLO-selective release by survivin. Oncogene. 2007;26:7569-7575.

    Not in our library10.1038/sj.onc.1210560

  85. 85.
    Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study? · 2019
    No notice
  86. 86.

    Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell. 2005;8:179-183.

    Not in our library10.1016/j.ccr.2005.08.008

  87. 87.

    Chen Y., Wang T., Du J., Li Y., Wang X., Zhou Y., Yu X., Fan W., Zhu Q., Tong X., et al. The Critical Role of PTEN/PI3K/AKT Signaling Pathway in Shikonin-Induced Apoptosis and Proliferation Inhibition of Chronic Myeloid Leukemia. Cell. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharmacol. 2018;47:981-993.

    Not in our library10.1159/000490142

  88. 88.

    Rahmani F., Ziaeemehr A., Shahidsales S., Gharib M., Khazaei M., Ferns G.A., Ryzhikov M., Avan A., Hassanian S.M. Role of regulatory miRNAs of the PI3K/AKT/mTOR signaling in the pathogenesis of hepatocellular carcinoma. J. Cell. Physiol. 2020;235:4146-4152.

    Not in our library10.1002/jcp.29333

  89. 89.

    Soltani A., Torki S., Ghahfarokhi M.S., Jami M.S., Ghatrehsamani M. Targeting the phosphoinositide 3-kinase/AKT pathways by small molecules and natural compounds as a therapeutic approach for breast cancer cells. Mol. Biol. Rep. 2019;46:4809-4816.

    Not in our library10.1007/s11033-019-04929-x

  90. 90.

    Ediriweera M.K., Tennekoon K.H., Samarakoon S.R. Role of the PI3K/AKT/mTOR signaling pathway in ovarian cancer: Biological and therapeutic significance. Semin. Cancer Biol. 2019;59:147-160.

    Not in our library10.1016/j.semcancer.2019.05.012

  91. 91.

    Wu D.M., Zhang T., Liu Y.B., Deng S.H., Han R., Liu T., Li J., Xu Y. The PAX6-ZEB2 axis promotes metastasis and cisplatin resistance in non-small cell lung cancer through PI3K/AKT signaling. Cell Death Dis. 2019;10:349.

    Not in our library10.1038/s41419-019-1591-4

  92. 92.

    Rittler D., Baranyi M., Molnar E., Garay T., Jalsovszky I., Varga I.K., Hegedus L., Aigner C., Tovari J., Timar J., et al. The Antitumor Effect of Lipophilic Bisphosphonate BPH1222 in Melanoma Models: The Role of the PI3K/Akt Pathway and the Small G Protein Rheb. Int. J. Mol. Sci. 2019;20:4917.

    Not in our library10.3390/ijms20194917

  93. 93.

    Fayard E., Tintignac L.A., Baudry A., Hemmings B.A. Protein kinase B/Akt at a glance. J. Cell Sci. 2005;118:5675-5678.

    Not in our library10.1242/jcs.02724

  94. 94.

    Stambolic V., Suzuki A., de la Pompa J.L., Brothers G.M., Mirtsos C., Sasaki T., Ruland J., Penninger J.M., Siderovski D.P., Mak T.W. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998;95:29-39.

    Not in our library10.1016/s0092-8674(00)81780-8

  95. 95.

    Vazquez F., Ramaswamy S., Nakamura N., Sellers W.R. Phosphorylation of the PTEN tail regulates protein stability and function. Mol. Cell Biol. 2000;20:5010-5018.

    Not in our library10.1128/mcb.20.14.5010-5018.2000

  96. 96.

    Stephens L., Anderson K., Stokoe D., Erdjument-Bromage H., Painter G.F., Holmes A.B., Gaffney P.R., Reese C.B., McCormick F., Tempst P., et al. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science. 1998;279:710-714.

    Not in our library10.1126/science.279.5351.710

  97. 97.

    Sarbassov D.D., Guertin D.A., Ali S.M., Sabatini D.M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307:1098-1101.

    Not in our library10.1126/science.1106148

  98. 98.

    Jacinto E., Facchinetti V., Liu D., Soto N., Wei S., Jung S.Y., Huang Q., Qin J., Su B. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell. 2006;127:125-137.

    Not in our library10.1016/j.cell.2006.08.033

  99. 99.

    Alessi D.R., Andjelkovic M., Caudwell B., Cron P., Morrice N., Cohen P., Hemmings B.A. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 1996;15:6541-6551.

    Not in our library10.1002/j.1460-2075.1996.tb01045.x

  100. 100.

    Carnero A., Blanco-Aparicio C., Renner O., Link W., Leal J.F. The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr. Cancer Drug Targets. 2008;8:187-198.

    Not in our library10.2174/156800908784293659

  101. 101.

    Sale E.M., Sale G.J. Protein kinase B: Signalling roles and therapeutic targeting. Cell Mol. Life Sci. 2008;65:113-127.

    Not in our library10.1007/s00018-007-7274-9

  102. 102.

    Asanuma H., Torigoe T., Kamiguchi K., Hirohashi Y., Ohmura T., Hirata K., Sato M., Sato N. Survivin expression is regulated by coexpression of human epidermal growth factor receptor 2 and epidermal growth factor receptor via phosphatidylinositol 3-kinase/AKT signaling pathway in breast cancer cells. Cancer Res. 2005;65:11018-11025.

    Not in our library10.1158/0008-5472.can-05-0491

  103. 103.

    Crawford A., Nahta R. Targeting Bcl-2 in Herceptin-Resistant Breast Cancer Cell Lines. Curr. Pharm. Pers. Med. 2011;9:184-190.

    Not in our library10.2174/187569211796957584

  104. 104.

    Du K., Montminy M. CREB is a regulatory target for the protein kinase Akt/PKB. J. Biol. Chem. 1998;273:32377-32379.

    Not in our library10.1074/jbc.273.49.32377

  105. 105.

    Song G., Ouyang G., Bao S. The activation of Akt/PKB signaling pathway and cell survival. J. Cell Mol. Med. 2005;9:59-71.

    Not in our library10.1111/j.1582-4934.2005.tb00337.x

  106. 106.
    PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers · 2020
    No notice
  107. 107.

    Welsh G.I., Wilson C., Proud C.G. GSK3: A SHAGGY frog story. Trends Cell Biol. 1996;6:274-279.

    Not in our library10.1016/0962-8924(96)10023-4

  108. 108.

    Srivastava A.K., Pandey S.K. Potential mechanism(s) involved in the regulation of glycogen synthesis by insulin. Mol. Cell Biochem. 1998;182:135-141.

    Not in our library10.1023/a:1006857527588

  109. 109.

    Diehl J.A., Cheng M., Roussel M.F., Sherr C.J. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 1998;12:3499-3511.

    Not in our library10.1101/gad.12.22.3499

  110. 110.

    Somanath P.R., Vijai J., Kichina J.V., Byzova T., Kandel E.S. The role of PAK-1 in activation of MAP kinase cascade and oncogenic transformation by Akt. Oncogene. 2009;28:2365-2369.

    Not in our library10.1038/onc.2009.114

  111. 111.

    Manning B.D., Cantley L.C. AKT/PKB signaling: Navigating downstream. Cell. 2007;129:1261-1274.

    Not in our library10.1016/j.cell.2007.06.009

  112. 112.

    Zhang X., Tang N., Hadden T.J., Rishi A.K. Akt, FoxO and regulation of apoptosis. Biochim. Biophys. Acta. 2011;1813:1978-1986.

    Not in our library10.1016/j.bbamcr.2011.03.010

  113. 113.

    Farhan M., Silva M., Xingan X., Huang Y., Zheng W. Role of FOXO Transcription Factors in Cancer Metabolism and Angiogenesis. Cells. 2020;9:1586.

    Not in our library10.3390/cells9071586

  114. 114.

    Slamon D.J., Clark G.M., Wong S.G., Levin W.J., Ullrich A., McGuire W.L. Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177-182.

    Not in our library10.1126/science.3798106

  115. 115.

    Zhou B.P., Hu M.C., Miller S.A., Yu Z., Xia W., Lin S.Y., Hung M.C. HER-2/neu blocks tumor necrosis factor-induced apoptosis via the Akt/NF-kappaB pathway. J. Biol. Chem. 2000;275:8027-8031.

    Not in our library10.1074/jbc.275.11.8027

  116. 116.

    Salomon D.S., Brandt R., Ciardiello F., Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit. Rev. Oncol. Hematol. 1995;19:183-232.

    Not in our library10.1016/1040-8428(94)00144-i

  117. 117.

    Shayesteh L., Lu Y., Kuo W.L., Baldocchi R., Godfrey T., Collins C., Pinkel D., Powell B., Mills G.B., Gray J.W. PIK3CA is implicated as an oncogene in ovarian cancer. Nat. Genet. 1999;21:99-102.

    Not in our library10.1038/5042

  118. 118.

    Byun D.S., Cho K., Ryu B.K., Lee M.G., Park J.I., Chae K.S., Kim H.J., Chi S.G. Frequent monoallelic deletion of PTEN and its reciprocal associatioin with PIK3CA amplification in gastric carcinoma. Int. J. Cancer. 2003;104:318-327.

    Not in our library10.1002/ijc.10962

  119. 119.

    Samuels Y., Diaz L.A., Schmidt-Kittler O., Cummins J.M., Delong L., Cheong I., Rago C., Huso D.L., Lengauer C., Kinzler K.W., et al. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell. 2005;7:561-573.

    Not in our library10.1016/j.ccr.2005.05.014

  120. 120.

    Stal O., Perez-Tenorio G., Akerberg L., Olsson B., Nordenskjold B., Skoog L., Rutqvist L.E. Akt kinases in breast cancer and the results of adjuvant therapy. Breast Cancer Res. 2003;5:R37-R44.

    Not in our library10.1186/bcr569

  121. 121.

    Roy H.K., Olusola B.F., Clemens D.L., Karolski W.J., Ratashak A., Lynch H.T., Smyrk T.C. AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. Carcinogenesis. 2002;23:201-205.

    Not in our library10.1093/carcin/23.1.201

  122. 122.
    AKT2 drives cancer progression and is negatively modulated by miR-124 in human lung adenocarcinoma · 2020
    Not checked
  123. 123.

    Rychahou P.G., Kang J., Gulhati P., Doan H.Q., Chen L.A., Xiao S.Y., Chung D.H., Evers B.M. Akt2 overexpression plays a critical role in the establishment of colorectal cancer metastasis. Proc. Natl. Acad. Sci. USA. 2008;105:20315-20320.

    Not in our library10.1073/pnas.0810715105

  124. 124.

    Arboleda M.J., Lyons J.F., Kabbinavar F.F., Bray M.R., Snow B.E., Ayala R., Danino M., Karlan B.Y., Slamon D.J. Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells. Cancer Res. 2003;63:196-206.

    Not in our library

  125. 125.

    Ozes O.N., Akca H., Mayo L.D., Gustin J.A., Maehama T., Dixon J.E., Donner D.B. A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1. Proc. Natl. Acad. Sci. USA. 2001;98:4640-4645.

    Not in our library10.1073/pnas.051042298

  126. 126.

    Osaki M., Oshimura M., Ito H. PI3K-Akt pathway: Its functions and alterations in human cancer. Apoptosis. 2004;9:667-676.

    Not in our library10.1023/b:appt.0000045801.15585.dd

  127. 127.
    The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities · 2021
    No notice
  128. 128.

    Neophytou C.M., Pierides C., Christodoulou M.I., Costeas P., Kyriakou T.C., Papageorgis P. The Role of Tumor-Associated Myeloid Cells in Modulating Cancer Therapy. Front. Oncol. 2020;10:899.

    Not in our library10.3389/fonc.2020.00899

  129. 129.

    Martinez-Lostao L., Anel A., Pardo J. How Do Cytotoxic Lymphocytes Kill Cancer Cells? Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2015;21:5047-5056.

    Not in our library10.1158/1078-0432.ccr-15-0685

  130. 130.

    Anel A., Buferne M., Boyer C., Schmitt-Verhulst A.M., Golstein P. T cell receptor-induced Fas ligand expression in cytotoxic T lymphocyte clones is blocked by protein tyrosine kinase inhibitors and cyclosporin A. Eur. J. Immunol. 1994;24:2469-2476.

    Not in our library10.1002/eji.1830241032

  131. 131.

    Bossi G., Griffiths G.M. CTL secretory lysosomes: Biogenesis and secretion of a harmful organelle. Semin. Immunol. 2005;17:87-94.

    Not in our library10.1016/j.smim.2004.09.007

  132. 132.

    De Saint Basile G., Menasche G., Fischer A. Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules. Nat. Rev. Immunol. 2010;10:568-579.

    Not in our library10.1038/nri2803

  133. 133.

    Tecchio C., Huber V., Scapini P., Calzetti F., Margotto D., Todeschini G., Pilla L., Martinelli G., Pizzolo G., Rivoltini L., et al. IFNalpha-stimulated neutrophils and monocytes release a soluble form of TNF-related apoptosis-inducing ligand (TRAIL/Apo-2 ligand) displaying apoptotic activity on leukemic cells. Blood. 2004;103:3837-3844.

    Not in our library10.1182/blood-2003-08-2806

  134. 134.

    Lee G.T., Kim J.H., Kwon S.J., Stein M.N., Hong J.H., Nagaya N., Billakanti S., Kim M.M., Kim W.J., Kim I.Y. Dihydrotestosterone Increases Cytotoxic Activity of Macrophages on Prostate Cancer Cells via TRAIL. Endocrinology. 2019;160:2049-2060.

    Not in our library10.1210/en.2019-00367

  135. 135.

    Freeman Z.T., Nirschl T.R., Hovelson D.H., Johnston R.J., Engelhardt J.J., Selby M.J., Kochel C.M., Lan R.Y., Zhai J., Ghasemzadeh A., et al. A conserved intratumoral regulatory T cell signature identifies 4-1BB as a pan-cancer target. J. Clin. Investig. 2020;130:1405-1416.

    Not in our library10.1172/jci128672

  136. 136.

    Hu B.S., Tang T., Jia J.L., Xie B.C., Wu T.L., Sheng Y.Y., Xue Y.Z., Tang H.M. CD137 agonist induces gastric cancer cell apoptosis by enhancing the functions of CD8(+) T cells via NF-kappaB signaling. Cancer Cell Int. 2020;20:513.

    Not in our library10.1186/s12935-020-01605-0

  137. 137.

    Yu D., Zhong Y., Li X., Li Y., Li X., Cao J., Fan H., Yuan Y., Ji Z., Qiao B., et al. ILs-3, 6 and 11 increase, but ILs-10 and 24 decrease stemness of human prostate cancer cells in vitro. Oncotarget. 2015;6:42687-42703.

    Not in our library10.18632/oncotarget.5883

  138. 138.

    Quail D.F., Joyce J.A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 2013;19:1423-1437.

    Not in our library10.1038/nm.3394

  139. 139.

    Bejarano L., Jordao M.J.C., Joyce J.A. Therapeutic Targeting of the Tumor Microenvironment. Cancer Discov. 2021;11:933-959.

    Not in our library10.1158/2159-8290.cd-20-1808

  140. 140.
    Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance · 2021
    No notice
  141. 141.

    Jain R.K., Martin J.D., Stylianopoulos T. The role of mechanical forces in tumor growth and therapy. Annu. Rev. Biomed. Eng. 2014;16:321-346.

    Not in our library10.1146/annurev-bioeng-071813-105259

  142. 142.

    Muz B., de la Puente P., Azab F., Azab A.K. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia. 2015;3:83-92.

    Not in our library10.2147/hp.s93413

  143. 143.

    Gerweck L.E., Vijayappa S., Kozin S. Tumor pH controls the in vivo efficacy of weak acid and base chemotherapeutics. Mol. Cancer Ther. 2006;5:1275-1279.

    Not in our library10.1158/1535-7163.mct-06-0024

  144. 144.

    Yamaguchi H., Sakai R. Direct Interaction between Carcinoma Cells and Cancer Associated Fibroblasts for the Regulation of Cancer Invasion. Cancers. 2015;7:2054-2062.

    Not in our library10.3390/cancers7040876

  145. 145.
    The Role of Cancer-Associated Fibroblasts in Tumor Progression · 2021
    No notice
  146. 146.
    Cancer-Associated Fibroblasts as Another Polarized Cell Type of the Tumor Microenvironment · 2014
    No notice
  147. 147.

    Guo L., Li B., Yang J., Shen J., Ji J., Miao M. Fibroblastderived exosomal microRNA369 potentiates migration and invasion of lung squamous cell carcinoma cells via NF1mediated MAPK signaling pathway. Int. J. Mol. Med. 2020;46:595-608.

    Not in our library10.3892/ijmm.2020.4614

  148. 148.

    Valcz G., Sipos F., Tulassay Z., Molnar B., Yagi Y. Importance of carcinoma-associated fibroblast-derived proteins in clinical oncology. J. Clin. Pathol. 2014;67:1026-1031.

    Not in our library10.1136/jclinpath-2014-202561

  149. 149.

    Paraiso K.H., Smalley K.S. Fibroblast-mediated drug resistance in cancer. Biochem. Pharmacol. 2013;85:1033-1041.

    Not in our library10.1016/j.bcp.2013.01.018

  150. 150.

    Choe C., Shin Y.S., Kim S.H., Jeon M.J., Choi S.J., Lee J., Kim J. Tumor-stromal interactions with direct cell contacts enhance motility of non-small cell lung cancer cells through the hedgehog signaling pathway. Anticancer Res. 2013;33:3715-3723.

    Not in our library

  151. 151.

    Ren J., Ding L., Zhang D., Shi G., Xu Q., Shen S., Wang Y., Wang T., Hou Y. Carcinoma-associated fibroblasts promote the stemness and chemoresistance of colorectal cancer by transferring exosomal lncRNA H19. Theranostics. 2018;8:3932-3948.

    Not in our library10.7150/thno.25541

  152. 152.

    Chen W.J., Ho C.C., Chang Y.L., Chen H.Y., Lin C.A., Ling T.Y., Yu S.L., Yuan S.S., Chen Y.J., Lin C.Y., et al. Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling. Nat. Commun. 2014;5:3472.

    Not in our library10.1038/ncomms4472

  153. 153.

    Lacina L., Plzak J., Kodet O., Szabo P., Chovanec M., Dvorankova B., Smetana K. Cancer Microenvironment: What Can We Learn from the Stem Cell Niche. Int. J. Mol. Sci. 2015;16:24094-24110.

    Not in our library10.3390/ijms161024094

  154. 154.

    Xi C., Wang J., Sun H., Zhang X., Kang H. Loss of microRNA-30e induced by extracellular vesicles from cancer-associated fibroblasts promotes breast cancer progression by binding to CTHRC1. Exp. Mol. Pathol. 2021;118:104586.

    Not in our library10.1016/j.yexmp.2020.104586

  155. 155.

    Eichelmann A.K., Matuszcak C., Hummel R., Haier J. Role of miRNAs in cell signaling of cancer associated fibroblasts. Int. J. Biochem. Cell Biol. 2018;101:94-102.

    Not in our library10.1016/j.biocel.2018.05.015

  156. 156.

    Boomgarden A.C., Sheehan C., D’Souza-Schorey C. Extracellular Vesicles in the Tumor Microenvironment: Various Implications in Tumor Progression. Adv. Exp. Med. Biol. 2020;1259:155-170.

    Not in our library10.1007/978-3-030-43093-1_9

  157. 157.

    Wang H., Wei H., Wang J., Li L., Chen A., Li Z. MicroRNA-181d-5p-Containing Exosomes Derived from CAFs Promote EMT by Regulating CDX2/HOXA5 in Breast Cancer. Mol. Ther. Nucleic Acids. 2020;19:654-667.

    Not in our library10.1016/j.omtn.2019.11.024

  158. 158.

    Beermann J., Piccoli M.T., Viereck J., Thum T. Non-coding RNAs in Development and Disease: Background, Mechanisms, and Therapeutic Approaches. Physiol. Rev. 2016;96:1297-1325.

    Not in our library10.1152/physrev.00041.2015

  159. 159.

    Di Martino M.T., Riillo C., Scionti F., Grillone K., Polera N., Caracciolo D., Arbitrio M., Tagliaferri P., Tassone P. miRNAs and lncRNAs as Novel Therapeutic Targets to Improve Cancer Immunotherapy. Cancers. 2021;13:1587.

    Not in our library10.3390/cancers13071587

  160. 160.

    Cui H., Onyango P., Brandenburg S., Wu Y., Hsieh C.L., Feinberg A.P. Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2. Cancer Res. 2002;62:6442-6446.

    Not in our library

  161. 161.

    Berteaux N., Lottin S., Monte D., Pinte S., Quatannens B., Coll J., Hondermarck H., Curgy J.J., Dugimont T., Adriaenssens E. H19 mRNA-like noncoding RNA promotes breast cancer cell proliferation through positive control by E2F1. J. Biol. Chem. 2005;280:29625-29636.

    Not in our library10.1074/jbc.m504033200

  162. 162.

    Lecerf C., Peperstraete E., Le Bourhis X., Adriaenssens E. Propagation and Maintenance of Cancer Stem Cells: A Major Influence of the Long Non-Coding RNA H19. Cells. 2020;9:2613.

    Not in our library10.3390/cells9122613

  163. 163.

    Vermeulen L., De Sousa E.M.F., van der Heijden M., Cameron K., de Jong J.H., Borovski T., Tuynman J.B., Todaro M., Merz C., Rodermond H., et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat. Cell Biol. 2010;12:468-476.

    Not in our library10.1038/ncb2048

  164. 164.

    Gao Z., Wang Q., Ji M., Guo X., Li L., Su X. Exosomal lncRNA UCA1 modulates cervical cancer stem cell self-renewal and differentiation through microRNA-122-5p/SOX2 axis. J. Transl. Med. 2021;19:229.

    Not in our library10.1186/s12967-021-02872-9

  165. 165.

    Lv X., Lian Y., Liu Z., Xiao J., Zhang D., Yin X. Exosomal long non-coding RNA LINC00662 promotes non-small cell lung cancer progression by miR-320d/E2F1 axis. Aging. 2021;13:6010-6024.

    Not in our library10.18632/aging.202522

  166. 166.
    Long non-coding RNAs regulate drug resistance in cancer · 2020
    No notice
  167. 167.

    Ying L., Zhu Z., Xu Z., He T., Li E., Guo Z., Liu F., Jiang C., Wang Q. Cancer Associated Fibroblast-Derived Hepatocyte Growth Factor Inhibits the Paclitaxel-Induced Apoptosis of Lung Cancer A549 Cells by Up-Regulating the PI3K/Akt and GRP78 Signaling on a Microfluidic Platform. PLoS ONE. 2015;10:e0129593.

    Not in our library10.1371/journal.pone.0129593

  168. 168.

    Chen C., Hou J., Yu S., Li W., Wang X., Sun H., Qin T., Claret F.X., Guo H., Liu Z. Role of cancer-associated fibroblasts in the resistance to antitumor therapy, and their potential therapeutic mechanisms in non-small cell lung cancer. Oncol. Lett. 2021;21:413.

    Not in our library10.3892/ol.2021.12674

  169. 169.
    Cancer-associated fibroblasts treated with cisplatin facilitates chemoresistance of lung adenocarcinoma through IL-11/IL-11R/STAT3 signaling pathway · 2016
    No notice
  170. 170.

    Bockhorn J., Dalton R., Nwachukwu C., Huang S., Prat A., Yee K., Chang Y.F., Huo D., Wen Y., Swanson K.E., et al. MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11. Nat. Commun. 2013;4:1393.

    Not in our library10.1038/ncomms2393

  171. 171.

    Lokau J., Agthe M., Garbers C. Generation of Soluble Interleukin-11 and Interleukin-6 Receptors: A Crucial Function for Proteases during Inflammation. Mediat. Inflamm. 2016;2016:1785021.

    Not in our library10.1155/2016/1785021

  172. 172.

    Delbridge A.R., Grabow S., Strasser A., Vaux D.L. Thirty years of BCL-2: Translating cell death discoveries into novel cancer therapies. Nat. Rev. Cancer. 2016;16:99-109.

    Not in our library10.1038/nrc.2015.17

  173. 173.

    Real P.J., Sierra A., De Juan A., Segovia J.C., Lopez-Vega J.M., Fernandez-Luna J.L. Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells. Oncogene. 2002;21:7611-7618.

    Not in our library10.1038/sj.onc.1206004

  174. 174.

    Borsellino N., Belldegrun A., Bonavida B. Endogenous interleukin 6 is a resistance factor for cis-diamminedichloroplatinum and etoposide-mediated cytotoxicity of human prostate carcinoma cell lines. Cancer Res. 1995;55:4633-4639.

    Not in our library

  175. 175.

    Garcia-Tunon I., Ricote M., Ruiz A., Fraile B., Paniagua R., Royuela M. IL-6, its receptors and its relationship with bcl-2 and bax proteins in infiltrating and in situ human breast carcinoma. Histopathology. 2005;47:82-89.

    Not in our library10.1111/j.1365-2559.2005.02178.x

  176. 176.

    Gritsko T., Williams A., Turkson J., Kaneko S., Bowman T., Huang M., Nam S., Eweis I., Diaz N., Sullivan D., et al. Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2006;12:11-19.

    Not in our library10.1158/1078-0432.ccr-04-1752

  177. 177.

    Kumari N., Dwarakanath B.S., Das A., Bhatt A.N. Role of interleukin-6 in cancer progression and therapeutic resistance. Tumour Biol. J. Int. Soc. Oncodev. Biol. Med. 2016;37:11553-11572.

    Not in our library10.1007/s13277-016-5098-7

  178. 178.

    Jiang X.P., Yang D.C., Elliott R.L., Head J.F. Down-regulation of expression of interleukin-6 and its receptor results in growth inhibition of MCF-7 breast cancer cells. Anticancer Res. 2011;31:2899-2906.

    Not in our library

  179. 179.

    So K.A., Min K.J., Hong J.H., Lee J.K. Interleukin-6 expression by interactions between gynecologic cancer cells and human mesenchymal stem cells promotes epithelial-mesenchymal transition. Int. J. Oncol. 2015;47:1451-1459.

    Not in our library10.3892/ijo.2015.3122

  180. 180.

    Kinoshita H., Hirata Y., Nakagawa H., Sakamoto K., Hayakawa Y., Takahashi R., Nakata W., Sakitani K., Serizawa T., Hikiba Y., et al. Interleukin-6 mediates epithelial-stromal interactions and promotes gastric tumorigenesis. PLoS ONE. 2013;8:e60914.

    Not in our library10.1371/journal.pone.0060914

  181. 181.
    IL-6 secreted by cancer-associated fibroblasts promotes epithelial-mesenchymal transition and metastasis of gastric cancer via JAK2/STAT3 signaling pathway · 2017
    No notice
  182. 182.
    Targeting interleukin-6 as a strategy to overcome stroma-induced resistance to chemotherapy in gastric cancer · 2019
    No notice
  183. 183.

    Ma Y., Zhu J., Chen S., Li T., Ma J., Guo S., Hu J., Yue T., Zhang J., Wang P., et al. Activated gastric cancer-associated fibroblasts contribute to the malignant phenotype and 5-FU resistance via paracrine action in gastric cancer. Cancer Cell Int. 2018;18:104.

    Not in our library10.1186/s12935-018-0599-7

  184. 184.

    Hwang R.F., Moore T., Arumugam T., Ramachandran V., Amos K.D., Rivera A., Ji B., Evans D.B., Logsdon C.D. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res. 2008;68:918-926.

    Not in our library10.1158/0008-5472.can-07-5714

  185. 185.

    Muerkoster S., Wegehenkel K., Arlt A., Witt M., Sipos B., Kruse M.L., Sebens T., Kloppel G., Kalthoff H., Folsch U.R., et al. Tumor stroma interactions induce chemoresistance in pancreatic ductal carcinoma cells involving increased secretion and paracrine effects of nitric oxide and interleukin-1beta. Cancer Res. 2004;64:1331-1337.

    Not in our library10.1158/0008-5472.can-03-1860

  186. 186.
    Tumor-related interleukins: old validated targets for new anti-cancer drug development · 2017
    No notice
  187. 187.

    Tripathi S.C., Fahrmann J.F., Celiktas M., Aguilar M., Marini K.D., Jolly M.K., Katayama H., Wang H., Murage E.N., Dennison J.B., et al. MCAM Mediates Chemoresistance in Small-Cell Lung Cancer via the PI3K/AKT/SOX2 Signaling Pathway. Cancer Res. 2017;77:4414-4425.

    Not in our library10.1158/0008-5472.can-16-2874

  188. 188.

    Jung K., Wang P., Gupta N., Gopal K., Wu F., Ye X., Alshareef A., Bigras G., McMullen T.P., Abdulkarim B.S., et al. Profiling gene promoter occupancy of Sox2 in two phenotypically distinct breast cancer cell subsets using chromatin immunoprecipitation and genome-wide promoter microarrays. Breast Cancer Res. 2014;16:470.

    Not in our library10.1186/s13058-014-0470-2

  189. 189.

    Srinivasan D., Senbanjo L., Majumdar S., Franklin R.B., Chellaiah M.A. Androgen receptor expression reduces stemness characteristics of prostate cancer cells (PC3) by repression of CD44 and SOX2. J. Cell. Biochem. 2018.

    Not in our library10.1002/jcb.27573

  190. 190.

    Gao H., Teng C., Huang W., Peng J., Wang C. SOX2 Promotes the Epithelial to Mesenchymal Transition of Esophageal Squamous Cells by Modulating Slug Expression through the Activation of STAT3/HIF-alpha Signaling. Int. J. Mol. Sci. 2015;16:21643-21657.

    Not in our library10.3390/ijms160921643

  191. 191.
    Sox2 promotes tamoxifen resistance in breast cancer cells · 2013
    No notice
  192. 192.

    Finicelli M., Benedetti G., Squillaro T., Pistilli B., Marcellusi A., Mariani P., Santinelli A., Latini L., Galderisi U., Giordano A. Expression of stemness genes in primary breast cancer tissues: The role of SOX2 as a prognostic marker for detection of early recurrence. Oncotarget. 2014;5:9678-9688.

    Not in our library10.18632/oncotarget.1936

  193. 193.

    Dittmer A., Dittmer J. Carcinoma-Associated Fibroblasts Promote Growth of Sox2-Expressing Breast Cancer Cells. Cancers. 2020;12:3435.

    Not in our library10.3390/cancers12113435

  194. 194.

    Shekhar M.P., Santner S., Carolin K.A., Tait L. Direct involvement of breast tumor fibroblasts in the modulation of tamoxifen sensitivity. Am. J. Pathol. 2007;170:1546-1560.

    Not in our library10.2353/ajpath.2007.061004

  195. 195.

    Zhang S., Sun Y. Targeting oncogenic SOX2 in human cancer cells: Therapeutic application. Protein Cell. 2020;11:82-84.

    Not in our library10.1007/s13238-019-00673-x

  196. 196.

    Deying W., Feng G., Shumei L., Hui Z., Ming L., Hongqing W. CAF-derived HGF promotes cell proliferation and drug resistance by up-regulating the c-Met/PI3K/Akt and GRP78 signalling in ovarian cancer cells. Biosci. Rep. 2017;37.

    Not in our library10.1042/bsr20160470

  197. 197.

    Moran-Jones K. The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer. Mol. Diagn. Ther. 2016;20:199-212.

    Not in our library10.1007/s40291-016-0201-8

  198. 198.

    Otte J.M., Schmitz F., Kiehne K., Stechele H.U., Banasiewicz T., Krokowicz P., Nakamura T., Folsch U.R., Herzig K. Functional expression of HGF and its receptor in human colorectal cancer. Digestion. 2000;61:237-246.

    Not in our library10.1159/000007764

  199. 199.

    Yamada T., Matsumoto K., Wang W., Li Q., Nishioka Y., Sekido Y., Sone S., Yano S. Hepatocyte growth factor reduces susceptibility to an irreversible epidermal growth factor receptor inhibitor in EGFR-T790M mutant lung cancer. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2010;16:174-183.

    Not in our library10.1158/1078-0432.ccr-09-1204

  200. 200.

    Meng Q., Xia C., Fang J., Rojanasakul Y., Jiang B.H. Role of PI3K and AKT specific isoforms in ovarian cancer cell migration, invasion and proliferation through the p70S6K1 pathway. Cell. Signal. 2006;18:2262-2271.

    Not in our library10.1016/j.cellsig.2006.05.019

  201. 201.

    Yao R., Cooper G.M. Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor. Science. 1995;267:2003-2006.

    Not in our library10.1126/science.7701324

  202. 202.

    Shin B.K., Wang H., Yim A.M., Le Naour F., Brichory F., Jang J.H., Zhao R., Puravs E., Tra J., Michael C.W., et al. Global profiling of the cell surface proteome of cancer cells uncovers an abundance of proteins with chaperone function. J. Biol. Chem. 2003;278:7607-7616.

    Not in our library10.1074/jbc.m210455200

  203. 203.

    Fu Y., Lee A.S. Glucose regulated proteins in cancer progression, drug resistance and immunotherapy. Cancer Biol. Ther. 2006;5:741-744.

    Not in our library10.4161/cbt.5.7.2970

  204. 204.

    Zhang J., Jiang Y., Jia Z., Li Q., Gong W., Wang L., Wei D., Yao J., Fang S., Xie K. Association of elevated GRP78 expression with increased lymph node metastasis and poor prognosis in patients with gastric cancer. Clin. Exp. Metastasis. 2006;23:401-410.

    Not in our library10.1007/s10585-006-9051-9

  205. 205.

    Davidson D.J., Haskell C., Majest S., Kherzai A., Egan D.A., Walter K.A., Schneider A., Gubbins E.F., Solomon L., Chen Z., et al. Kringle 5 of human plasminogen induces apoptosis of endothelial and tumor cells through surface-expressed glucose-regulated protein 78. Cancer Res. 2005;65:4663-4672.

    Not in our library10.1158/0008-5472.can-04-3426

  206. 206.

    Arnaudeau S., Arboit P., Bischof P., Shin-ya K., Tomida A., Tsuruo T., Irion O., Cohen M. Glucose-regulated protein 78: A new partner of p53 in trophoblast. Proteomics. 2009;9:5316-5327.

    Not in our library10.1002/pmic.200800865

  207. 207.

    Fu Y., Li J., Lee A.S. GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen starvation-induced apoptosis. Cancer Res. 2007;67:3734-3740.

    Not in our library10.1158/0008-5472.can-06-4594

  208. 208.

    Zhou H., Zhang Y., Fu Y., Chan L., Lee A.S. Novel mechanism of anti-apoptotic function of 78-kDa glucose-regulated protein (GRP78): Endocrine resistance factor in breast cancer, through release of B-cell lymphoma 2 (BCL-2) from BCL-2-interacting killer (BIK). J. Biol. Chem. 2011;286:25687-25696.

    Not in our library10.1074/jbc.m110.212944

  209. 209.

    Hao Y., Zhang L., He J., Guo Z., Ying L., Xu Z., Zhang J., Lu J., Wang Q. Functional investigation of NCI-H460-inducible myofibroblasts on the chemoresistance to VP-16 with a microfluidic 3D co-culture device. PLoS ONE. 2013;8:e61754.

    Not in our library10.1371/journal.pone.0061754

  210. 210.

    Zhou B., Sun C., Li N., Shan W., Lu H., Guo L., Guo E., Xia M., Weng D., Meng L., et al. Cisplatin-induced CCL5 secretion from CAFs promotes cisplatin-resistance in ovarian cancer via regulation of the STAT3 and PI3K/Akt signaling pathways. Int. J. Oncol. 2016;48:2087-2097.

    Not in our library10.3892/ijo.2016.3442

  211. 211.

    Mehlen P., Delloye-Bourgeois C., Chedotal A. Novel roles for Slits and netrins: Axon guidance cues as anticancer targets? Nat. Rev. Cancer. 2011;11:188-197.

    Not in our library10.1038/nrc3005

  212. 212.

    Kefeli U., Ucuncu Kefeli A., Cabuk D., Isik U., Sonkaya A., Acikgoz O., Ozden E., Uygun K. Netrin-1 in cancer: Potential biomarker and therapeutic target? Tumour Biol. 2017;39:1010428317698388.

    Not in our library10.1177/1010428317698388

  213. 213.

    Sung P.J., Rama N., Imbach J., Fiore S., Ducarouge B., Neves D., Chen H.W., Bernard D., Yang P.C., Bernet A., et al. Cancer-Associated Fibroblasts Produce Netrin-1 to Control Cancer Cell Plasticity. Cancer Res. 2019;79:3651-3661.

    Not in our library10.1158/0008-5472.can-18-2952

  214. 214.

    Adams C., Cazzanelli G., Rasul S., Hitchinson B., Hu Y., Coombes R.C., Raguz S., Yague E. Apoptosis inhibitor TRIAP1 is a novel effector of drug resistance. Oncol. Rep. 2015;34:415-422.

    Not in our library10.3892/or.2015.3988

  215. 215.

    Park W.R., Nakamura Y. p53CSV, a novel p53-inducible gene involved in the p53-dependent cell-survival pathway. Cancer Res. 2005;65:1197-1206.

    Not in our library10.1158/0008-5472.can-04-3339

  216. 216.

    Ketteler J., Panic A., Reis H., Wittka A., Maier P., Herskind C., Yague E., Jendrossek V., Klein D. Progression-Related Loss of Stromal Caveolin 1 Levels Mediates Radiation Resistance in Prostate Carcinoma via the Apoptosis Inhibitor TRIAP1. J. Clin. Med. 2019;8:348.

    Not in our library10.3390/jcm8030348

  217. 217.
    Overexpression of Mitochondria Mediator Gene TRIAP1 by miR-320b Loss Is Associated with Progression in Nasopharyngeal Carcinoma. · 2016
    Not checked
  218. 218.

    Kunou S., Shimada K., Takai M., Sakamoto A., Aoki T., Hikita T., Kagaya Y., Iwamoto E., Sanada M., Shimada S., et al. Exosomes secreted from cancer-associated fibroblasts elicit anti-pyrimidine drug resistance through modulation of its transporter in malignant lymphoma. Oncogene. 2021;40:3989-4003.

    Not in our library10.1038/s41388-021-01829-y

  219. 219.

    Staiger A.M., Duppel J., Dengler M.A., van der Kuip H., Vohringer M.C., Aulitzky W.E., Rosenwald A., Ott G., Horn H. An analysis of the role of follicular lymphoma-associated fibroblasts to promote tumor cell viability following drug-induced apoptosis. Leuk. Lymphoma. 2017;58:1922-1930.

    Not in our library10.1080/10428194.2016.1263841

  220. 220.

    Brien G., Trescol-Biemont M.C., Bonnefoy-Berard N. Downregulation of Bfl-1 protein expression sensitizes malignant B cells to apoptosis. Oncogene. 2007;26:5828-5832.

    Not in our library10.1038/sj.onc.1210363

  221. 221.

    Scarfo L., Ghia P. Reprogramming cell death: BCL2 family inhibition in hematological malignancies. Immunol. Lett. 2013;155:36-39.

    Not in our library10.1016/j.imlet.2013.09.015

  222. 222.

    Zhang H., Okamoto M., Panzhinskiy E., Zawada W.M., Das M. PKCdelta/midkine pathway drives hypoxia-induced proliferation and differentiation of human lung epithelial cells. Am. J. Physiol. Cell Physiol. 2014;306:C648-C658.

    Not in our library10.1152/ajpcell.00351.2013

  223. 223.

    Wang Q.L., Wang H., Zhao S.L., Huang Y.H., Hou Y.Y. Over-expressed and truncated midkines promote proliferation of BGC823 cells in vitro and tumor growth in vivo. World J. Gastroenterol. 2008;14:1858-1865.

    Not in our library10.3748/wjg.14.1858

  224. 224.

    Huang Y., Hoque M.O., Wu F., Trink B., Sidransky D., Ratovitski E.A. Midkine induces epithelial-mesenchymal transition through Notch2/Jak2-Stat3 signaling in human keratinocytes. Cell Cycle. 2008;7:1613-1622.

    Not in our library10.4161/cc.7.11.5952

  225. 225.

    Zhao G., Nie Y., Lv M., He L., Wang T., Hou Y. ERbeta-mediated estradiol enhances epithelial mesenchymal transition of lung adenocarcinoma through increasing transcription of midkine. Mol. Endocrinol. 2012;26:1304-1315.

    Not in our library10.1210/me.2012-1028

  226. 226.

    Zhang D., Ding L., Li Y., Ren J., Shi G., Wang Y., Zhao S., Ni Y., Hou Y. Midkine derived from cancer-associated fibroblasts promotes cisplatin-resistance via up-regulation of the expression of lncRNA ANRIL in tumour cells. Sci. Rep. 2017;7:16231.

    Not in our library10.1038/s41598-017-13431-y

  227. 227.

    Lorente M., Torres S., Salazar M., Carracedo A., Hernandez-Tiedra S., Rodriguez-Fornes F., Garcia-Taboada E., Melendez B., Mollejo M., Campos-Martin Y., et al. Stimulation of the midkine/ALK axis renders glioma cells resistant to cannabinoid antitumoral action. Cell Death Differ. 2011;18:959-973.

    Not in our library10.1038/cdd.2010.170

  228. 228.

    O’Brien S.M., Cunningham C.C., Golenkov A.K., Turkina A.G., Novick S.C., Rai K.R. Phase I to II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in patients with advanced chronic lymphocytic leukemia. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2005;23:7697-7702.

    Not in our library10.1200/jco.2005.02.4364

  229. 229.

    O’Brien S., Moore J.O., Boyd T.E., Larratt L.M., Skotnicki A., Koziner B., Chanan-Khan A.A., Seymour J.F., Bociek R.G., Pavletic S., et al. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2007;25:1114-1120.

    Not in our library10.1200/jco.2006.07.1191

  230. 230.

    Soderquist R.S., Eastman A. BCL2 Inhibitors as Anticancer Drugs: A Plethora of Misleading BH3 Mimetics. Mol. Cancer Ther. 2016;15:2011-2017.

    Not in our library10.1158/1535-7163.mct-16-0031

  231. 231.

    Wang J.Q., Li J.Y., Teng Q.X., Lei Z.N., Ji N., Cui Q., Zeng L., Pan Y., Yang D.H., Chen Z.S. Venetoclax, a BCL-2 Inhibitor, Enhances the Efficacy of Chemotherapeutic Agents in Wild-Type ABCG2-Overexpression-Mediated MDR Cancer Cells. Cancers. 2020;12:466.

    Not in our library10.3390/cancers12020466

  232. 232.

    Fang H., Harned T.M., Kalous O., Maldonado V., DeClerck Y.A., Reynolds C.P. Synergistic activity of fenretinide and the Bcl-2 family protein inhibitor ABT-737 against human neuroblastoma. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2011;17:7093-7104.

    Not in our library10.1158/1078-0432.ccr-11-0578

  233. 233.

    Chen L., Zhao Y., Halliday G.C., Berry P., Rousseau R.F., Middleton S.A., Nichols G.L., Del Bello F., Piergentili A., Newell D.R., et al. Structurally diverse MDM2-p53 antagonists act as modulators of MDR-1 function in neuroblastoma. Br. J. Cancer. 2014;111:716-725.

    Not in our library10.1038/bjc.2014.325

  234. 234.
    MDM2 Inhibition Sensitizes Prostate Cancer Cells to Androgen Ablation and Radiotherapy in a p53-Dependent Manner · 2016
    Not checked
  235. 235.

    Bai J., Wang R.-H., Qiao Y., Wang A., Fang C.-J. Schiff base derived from thiosemicarbazone and anthracene showed high potential in overcoming multidrug resistance in vitro with low drug resistance index. Drug Des. Devel. Ther. 2017;11:2227-2237.

    Not in our library10.2147/dddt.s138371

  236. 236.

    Zhang Y., Qu X.J., Liu Y.P., Yang X.H., Hou K.Z., Teng Y.E., Zhang J.D. Reversal effect of PI3-K inhibitor LY294002 on P-glycoprotein-mediated multidrug resistance of human leukemia cell line K562/DNR and gastric cancer cell line SGC7901/ADR. Ai Zheng Aizheng Chin. J. Cancer. 2009;28:97-99.

    Not in our library

  237. 237.

    Xue C., Wang C., Sun Y., Meng Q., Liu Z., Huo X., Sun P., Sun H., Ma X., Ma X., et al. Targeting P-glycoprotein function, p53 and energy metabolism: Combination of metformin and 2-deoxyglucose reverses the multidrug resistance of MCF-7/Dox cells to doxorubicin. Oncotarget. 2017;8:8622-8632.

    Not in our library10.18632/oncotarget.14373

  238. 238.

    Durrant D.E., Das A., Dyer S., Kukreja R.C. A dual PI3 kinase/mTOR inhibitor BEZ235 reverses doxorubicin resistance in ABCB1 overexpressing ovarian and pancreatic cancer cell lines. Biochim. Biophys. Acta Gen. Subj. 2020;1864:129556.

    Not in our library10.1016/j.bbagen.2020.129556

  239. 239.

    Caumanns J.J., Berns K., Wisman G.B.A., Fehrmann R.S.N., Tomar T., Klip H., Meersma G.J., Hijmans E.M., Gennissen A.M.C., Duiker E.W., et al. Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2018;24:3928-3940.

    Not in our library10.1158/1078-0432.ccr-17-3060

  240. 240.

    Ghayad S.E., Bieche I., Vendrell J.A., Keime C., Lidereau R., Dumontet C., Cohen P.A. mTOR inhibition reverses acquired endocrine therapy resistance of breast cancer cells at the cell proliferation and gene-expression levels. Cancer Sci. 2008;99:1992-2003.

    Not in our library10.1111/j.1349-7006.2008.00955.x

  241. 241.

    Voges Y., Michaelis M., Rothweiler F., Schaller T., Schneider C., Politt K., Mernberger M., Nist A., Stiewe T., Wass M.N., et al. Effects of YM155 on survivin levels and viability in neuroblastoma cells with acquired drug resistance. Cell Death Dis. 2016;7:e2410.

    Not in our library10.1038/cddis.2016.257

  242. 242.

    Yang L., Wang Q., Li D., Zhou Y., Zheng X., Sun H., Yan J., Zhang L., Lin Y., Wang X. Wogonin enhances antitumor activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo through ROS-mediated downregulation of cFLIPL and IAP proteins. Apoptosis. 2013;18:618-626.

    Not in our library10.1007/s10495-013-0808-8

  243. 243.

    Rao P.S., Satelli A., Moridani M., Jenkins M., Rao U.S. Luteolin induces apoptosis in multidrug resistant cancer cells without affecting the drug transporter function: Involvement of cell line-specific apoptotic mechanisms. Int. J. Cancer. 2012;130:2703-2714.

    Not in our library10.1002/ijc.26308

  244. 244.

    Jeng L.B., Kumar Velmurugan B., Chen M.C., Hsu H.H., Ho T.J., Day C.H., Lin Y.M., Padma V.V., Tu C.C., Huang C.Y. Fisetin mediated apoptotic cell death in parental and Oxaliplatin/irinotecan resistant colorectal cancer cells in vitro and in vivo. J. Cell. Physiol. 2018;233:7134-7142.

    Not in our library10.1002/jcp.26532

  245. 245.

    Li Y., Ahmed F., Ali S., Philip P.A., Kucuk O., Sarkar F.H. Inactivation of nuclear factor kappaB by soy isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic agents in human cancer cells. Cancer Res. 2005;65:6934-6942.

    Not in our library10.1158/0008-5472.can-04-4604

  246. 246.

    Yang S., Li W., Sun H., Wu B., Ji F., Sun T., Chang H., Shen P., Wang Y., Zhou D. Resveratrol elicits anti-colorectal cancer effect by activating miR-34c-KITLG in vitro and in vivo. BMC Cancer. 2015;15:969.

    Not in our library10.1186/s12885-015-1958-6

  247. 247.

    Zhao W., Bao P., Qi H., You H. Resveratrol down-regulates survivin and induces apoptosis in human multidrug-resistant SPC-A-1/CDDP cells. Oncol. Rep. 2010;23:279-286.

    Not in our library10.3892/or_00000634

  248. 248.

    Kunnumakkara A.B., Diagaradjane P., Anand P., Harikumar K.B., Deorukhkar A., Gelovani J., Guha S., Krishnan S., Aggarwal B.B. Curcumin sensitizes human colorectal cancer to capecitabine by modulation of cyclin D1, COX-2, MMP-9, VEGF and CXCR4 expression in an orthotopic mouse model. Int. J. Cancer. 2009;125:2187-2197.

    Not in our library10.1002/ijc.24593

  249. 249.
    Difluorinated-Curcumin (CDF) Restores PTEN Expression in Colon Cancer Cells by Down-Regulating miR-21 · 2013
    No notice
  250. 250.

    Wang S., Chen R., Zhong Z., Shi Z., Chen M., Wang Y. Epigallocatechin-3-gallate potentiates the effect of curcumin in inducing growth inhibition and apoptosis of resistant breast cancer cells. Am. J. Chin. Med. 2014;42:1279-1300.

    Not in our library10.1142/s0192415x14500803

  251. 251.

    Kao T.Y., Chung Y.C., Hou Y.C., Tsai Y.W., Chen C.H., Chang H.P., Chou J.L., Hsu C.P. Effects of ellagic acid on chemosensitivity to 5-fluorouracil in colorectal carcinoma cells. Anticancer Res. 2012;32:4413-4418.

    Not in our library

  252. 252.

    Wang H., Jia X.H., Chen J.R., Wang J.Y., Li Y.J. Osthole shows the potential to overcome P-glycoproteinmediated multidrug resistance in human myelogenous leukemia K562/ADM cells by inhibiting the PI3K/Akt signaling pathway. Oncol. Rep. 2016;35:3659-3668.

    Not in our library10.3892/or.2016.4730

  253. 253.

    Neophytou C.M., Constantinou C., Papageorgis P., Constantinou A.I. D-alpha-tocopheryl polyethylene glycol succinate (TPGS) induces cell cycle arrest and apoptosis selectively in Survivin-overexpressing breast cancer cells. Biochem. Pharm. 2014;89:31-42.

    Not in our library10.1016/j.bcp.2014.02.003

  254. 254.
    The anti-fibrotic agent pirfenidone synergizes with cisplatin in killing tumor cells and cancer-associated fibroblasts · 2016
    No notice
  255. 255.

    Wei S.C., Anang N.A.S., Sharma R., Andrews M.C., Reuben A., Levine J.H., Cogdill A.P., Mancuso J.J., Wargo J.A., Pe’er D., et al. Combination anti-CTLA-4 plus anti-PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies. Proc. Natl. Acad. Sci. USA. 2019;116:22699-22709.

    Not in our library10.1073/pnas.1821218116

  256. 256.

    Chen N., Fang W., Zhan J., Hong S., Tang Y., Kang S., Zhang Y., He X., Zhou T., Qin T., et al. Upregulation of PD-L1 by EGFR Activation Mediates the Immune Escape in EGFR-Driven NSCLC: Implication for Optional Immune Targeted Therapy for NSCLC Patients with EGFR Mutation. J. Thorac. Oncol. Off. Publ. Int. Assoc. Study Lung Cancer. 2015;10:910-923.

    Not in our library10.1097/jto.0000000000000500

  257. 257.

    Hay C.M., Sult E., Huang Q., Mulgrew K., Fuhrmann S.R., McGlinchey K.A., Hammond S.A., Rothstein R., Rios-Doria J., Poon E., et al. Targeting CD73 in the tumor microenvironment with MEDI9447. Oncoimmunology. 2016;5:e1208875.

    Not in our library10.1080/2162402x.2016.1208875

  258. 258.

    Soto H., Sanchez K., Escobar J.Y., Constanzo A., Fernandez Z., Melendez C. Cost-Effectiveness Analysis of Hydralazine and Magnesium Valproate LP Associated with Treatment for Adult Patients with Metastatic Recurrent or Persistent Cervical Cancer in Mexico. Value Health J. Int. Soc. Pharm. Outcomes Res. 2014;17:A639.

    Not in our library10.1016/j.jval.2014.08.2300

  259. 259.

    Dawood M., Ooko E., Efferth T. Collateral Sensitivity of Parthenolide via NF-kappaB and HIF-alpha Inhibition and Epigenetic Changes in Drug-Resistant Cancer Cell Lines. Front. Pharm. 2019;10:542.

    Not in our library10.3389/fphar.2019.00542

  260. 260.

    Xia C., Leon-Ferre R., Laux D., Deutsch J., Smith B.J., Frees M., Milhem M. Treatment of resistant metastatic melanoma using sequential epigenetic therapy (decitabine and panobinostat) combined with chemotherapy (temozolomide). Cancer Chemother. Pharmacol. 2014;74:691-697.

    Not in our library10.1007/s00280-014-2501-1

  261. 261.

    Falchook G.S., Fu S., Naing A., Hong D.S., Hu W., Moulder S., Wheler J.J., Sood A.K., Bustinza-Linares E., Parkhurst K.L., et al. Methylation and histone deacetylase inhibition in combination with platinum treatment in patients with advanced malignancies. Invest. New Drugs. 2013;31:1192-1200.

    Not in our library10.1007/s10637-013-0003-3

  262. 262.

    Sun C., Yin J., Fang Y., Chen J., Jeong K.J., Chen X., Vellano C.P., Ju Z., Zhao W., Zhang D., et al. BRD4 Inhibition Is Synthetic Lethal with PARP Inhibitors through the Induction of Homologous Recombination Deficiency. Cancer Cell. 2018;33:401-416.e408.

    Not in our library10.1016/j.ccell.2018.01.019

  263. 263.

    Shariati M., Meric-Bernstam F. Targeting AKT for cancer therapy. Expert Opin. Investig. Drugs. 2019;28:977-988.

    Not in our library10.1080/13543784.2019.1676726

  264. 264.

    Nitulescu G.M., Margina D., Juzenas P., Peng Q., Olaru O.T., Saloustros E., Fenga C., Spandidos D., Libra M., Tsatsakis A.M. Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review). Int. J. Oncol. 2016;48:869-885.

    Not in our library10.3892/ijo.2015.3306

  265. 265.
    The role of cellular reactive oxygen species in cancer chemotherapy · 2018
    No notice
  266. 266.

    Minassian L.M., Cotechini T., Huitema E., Graham C.H. Hypoxia-Induced Resistance to Chemotherapy in Cancer. Adv. Exp. Med. Biol. 2019;1136:123-139.

    Not in our library10.1007/978-3-030-12734-3_9

  267. 267.

    Li L., Xu J., Min T., Huang W. Up-regulation of P-glycoprotein expression by catalase via JNK activation in HepG2 cells. Redox Rep. Commun. Free Radic. Res. 2006;11:173-178.

    Not in our library10.1179/135100006x116682

  268. 268.
    Dietary phytochemicals and cancer chemoprevention: a review of the clinical evidence · 2016
    No notice
  269. 269.

    Neophytou C.M., Constantinou G.Y., Pezzuto J.M., Vang O. Pro-apoptotic properties of chemopreventive agents. Natural Products for Cancer Chemoprevention: Single Compounds and Combinations. 2020;517-559.

    Not in our library

  270. 270.

    Hu-Lieskovan S., Malouf G.G., Jacobs I., Chou J., Liu L., Johnson M.L. Addressing resistance to immune checkpoint inhibitor therapy: An urgent unmet need. Future Oncol. 2021;17:1401-1439.

    Not in our library10.2217/fon-2020-0967

  271. 271.

    Wilting R.H., Dannenberg J.H. Epigenetic mechanisms in tumorigenesis, tumor cell heterogeneity and drug resistance. Drug Resist. Updates Rev. Comment. Antimicrob. Anticancer Chemother. 2012;15:21-38.

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

  272. 272.

    Talukdar S., Bhoopathi P., Emdad L., Das S., Sarkar D., Fisher P.B. Dormancy and cancer stem cells: An enigma for cancer therapeutic targeting. Adv. Cancer Res. 2019;141:43-84.

    Not in our library10.1016/bs.acr.2018.12.002

  273. 273.

    Shipitsin M., Campbell L.L., Argani P., Weremowicz S., Bloushtain-Qimron N., Yao J., Nikolskaya T., Serebryiskaya T., Beroukhim R., Hu M., et al. Molecular definition of breast tumor heterogeneity. Cancer Cell. 2007;11:259-273.

    Not in our library10.1016/j.ccr.2007.01.013

  274. 274.

    Issa M.E., Takhsha F.S., Chirumamilla C.S., Perez-Novo C., Vanden Berghe W., Cuendet M. Epigenetic strategies to reverse drug resistance in heterogeneous multiple myeloma. Clin. Epigenet. 2017;9:17.

    Not in our library10.1186/s13148-017-0319-5

  275. 275.
    Epigenetic regulation in human cancer: the potential role of epi-drug in cancer therapy · 2020
    No notice
  276. 276.
    The timeline of epigenetic drug discovery: from reality to dreams · 2019
    No notice
  277. 277.
    Epigenetic heterogeneity in cancer · 2019
    No notice
  278. 278.

    Dawson M.A. The cancer epigenome: Concepts, challenges, and therapeutic opportunities. Science. 2017;355:1147-1152.

    Not in our library10.1126/science.aam7304

  279. 279.

    Mohammad H.P., Barbash O., Creasy C.L. Targeting epigenetic modifications in cancer therapy: Erasing the roadmap to cancer. Nat. Med. 2019;25:403-418.

    Not in our library10.1038/s41591-019-0376-8

  280. 280.

    Guo L., Lee Y.T., Zhou Y., Huang Y. Targeting epigenetic regulatory machinery to overcome cancer therapy resistance. Semin. Cancer Biol. 2021.

    Not in our library10.1016/j.semcancer.2020.12.022

  281. 281.

    Brown R., Curry E., Magnani L., Wilhelm-Benartzi C.S., Borley J. Poised epigenetic states and acquired drug resistance in cancer. Nat. Rev. Cancer. 2014;14:747-753.

    Not in our library10.1038/nrc3819

  282. 282.
    Mechanisms of Multidrug Resistance in Cancer Chemotherapy · 2020
    No notice
  283. 283.

    Juergens R.A., Wrangle J., Vendetti F.P., Murphy S.C., Zhao M., Coleman B., Sebree R., Rodgers K., Hooker C.M., Franco N., et al. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov. 2011;1:598-607.

    Not in our library10.1158/2159-8290.cd-11-0214

  284. 284.

    Fuller M., Klein M., Schmidt E., Rohde C., Gollner S., Schulze I., Qianli J., Berdel W.E., Edemir B., Muller-Tidow C., et al. 5-azacytidine enhances efficacy of multiple chemotherapy drugs in AML and lung cancer with modulation of CpG methylation. Int. J. Oncol. 2015;46:1192-1204.

    Not in our library10.3892/ijo.2014.2792

  285. 285.

    Hammerlindl H., Schaider H. Tumor cell-intrinsic phenotypic plasticity facilitates adaptive cellular reprogramming driving acquired drug resistance. J. Cell Commun. Signal. 2018;12:133-141.

    Not in our library10.1007/s12079-017-0435-1

  286. 286.

    Guha M. HDAC inhibitors still need a home run, despite recent approval. Nat. Rev. Drug Discov. 2015;14:225-226.

    Not in our library10.1038/nrd4583

  287. 287.

    Imamura Y., Mukohara T., Shimono Y., Funakoshi Y., Chayahara N., Toyoda M., Kiyota N., Takao S., Kono S., Nakatsura T., et al. Comparison of 2D- and 3D-culture models as drug-testing platforms in breast cancer. Oncol. Rep. 2015;33:1837-1843.

    Not in our library10.3892/or.2015.3767

  288. 288.

    Gengenbacher N., Singhal M., Augustin H.G. Preclinical mouse solid tumour models: Status quo, challenges and perspectives. Nat. Rev. Cancer. 2017;17:751-765.

    Not in our library10.1038/nrc.2017.92

  289. 289.
    Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells · 2016
    No notice
  290. 290.

    Boumahdi S., de Sauvage F.J. The great escape: Tumour cell plasticity in resistance to targeted therapy. Nat. Rev. Drug Discov. 2020;19:39-56.

    Not in our library10.1038/s41573-019-0044-1

  291. 291.

    Morel D., Jeffery D., Aspeslagh S., Almouzni G., Postel-Vinay S. Combining epigenetic drugs with other therapies for solid tumours—Past lessons and future promise. Nat. Rev. Clin. Oncol. 2020;17:91-107.

    Not in our library10.1038/s41571-019-0267-4

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