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Biochemical Pharmacology (v.83, #8)
Sensitization of tumor cells by targeting histone deacetylases
by Paola Perego; Valentina Zuco; Laura Gatti; Franco Zunino (pp. 987-994).
Epigenetic mechanisms may contribute to drug resistance by interfering with tumor growth regulatory pathways and pro-apoptotic programs. Since gene expression is regulated by acetylation status of histones, a large variety of histone deacetylase (HDAC) inhibitors have been studied as antitumor agents. On the basis of their pro-apoptotic activity, HDAC inhibitors have been combined with conventional antitumor agents or novel target-specific agents to increase susceptibility to apoptosis and drug sensitivity of cancer cells. Several combination strategies including HDAC inhibitors have been explored in preclinical studies. Promising therapeutic effects have been reported in combination with DNA damaging agents, taxanes, targeted agents, death receptor agonists and hormonal therapies. Some histone deacetylases, such as HDAC6, can also modulate the function of non-histone proteins involved in critical regulatory processes which may be relevant as therapeutic targets. Given the pleiotropic effects of most of the available inhibitors, the mechanisms of the sensitization are not completely elucidated. A better understanding of the involved mechanisms will provide a rational basis to improve the therapeutic outcome of the available antitumor agents.
Keywords: Drug resistance; Apoptosis; Histone deacetylases
Hsp90 inhibitors and drug resistance in cancer: The potential benefits of combination therapies of Hsp90 inhibitors and other anti-cancer drugs
by Xiangyi Lu; Li Xiao; Luan Wang; Douglas M. Ruden (pp. 995-1004).
Hsp90 is a chaperone protein that interacts with client proteins that are known to be in the cell cycle, signaling and chromatin-remodeling pathways. Hsp90 inhibitors act additively or synergistically with many other drugs in the treatment of both solid tumors and leukemias in murine tumor models and humans. Hsp90 inhibitors potentiate the actions of anti-cancer drugs that target Hsp90 client proteins, including trastuzumab (Herceptin™) which targets Her2/Erb2B, as Hsp90 inhibition elicits the drug effects in cancer cell lines that are otherwise resistant to the drug. A phase II study of the Hsp90 inhibitor 17-AAG and trastuzumab showed that this combination therapy has anticancer activity in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. In this review, we discuss the results of Hsp90 inhibitors in combination with trastuzumab and other cancer drugs. We also discuss recent results from yeast focused on the genetics of drug resistance when Hsp90 is inhibited and the implications that this might have in understanding the effects of genetic variation in treating cancer in humans.
Keywords: Hsp90; Cancer; Drug resistance; Geldanamycin
The role of glutathione in brain tumor drug resistance
by Donald S. Backos; Christopher C. Franklin; Philip Reigan (pp. 1005-1012).
The glutathione (GSH) biosynthetic pathway in brain tumors. (A) Most brain tumors arise from 3 main cell types or their progenitors: neurons (green), oligodendrocytes (cyan), and astrocytes (magenta). (B) GSH biosynthesis consists of two ATP-dependent reactions: (1) glutamate cysteine ligase (GCL)-mediated formation of γ-glutamyl-cysteine (γGluCys) from glutamate (Glu) and cysteine (Cys) and (2) GSH synthetase (GS)-catalyzed formation of GSH from γGluCys and glycine (Gly). Buthionine sulfoximine (BSO) is an irreversible inhibitor of GCL. Detoxification of chemotherapeutic agents proceeds via the GSH-S-transferase (GST)-mediated formation of GSH-drug conjugates (GSH-X) followed by efflux by multidrug resistance protein (Mrp) transporters. γ-Glutamyl transpeptidase (γGT) can break GSH down into Glu and cysteinylglycine (CysGly). CysGly is further hydrolyzed by cellular dipeptidases (DP) followed by the transporter-mediated uptake of the constituent amino acids that can serve as substrates for either cellular GSH production or protein synthesis. Additional Cys may also be obtained via the glutamate-cystine antiporter (Xc-)-mediated uptake of extracellular cystine (CysCys).Chemotherapy is central to the current treatment modality for primary human brain tumors, but despite high-dose and intensive treatment regimens there has been little improvement in patient outcome. The development of tumor chemoresistance has been proposed as a major contributor to this lack of response. While there have been some improvements in our understanding of the molecular mechanisms underlying brain tumor drug resistance over the past decade, the contribution of glutathione (GSH) and the GSH-related enzymes to drug resistance in brain tumors have been largely overlooked. GSH constitutes a major antioxidant defense system in the brain and together with the GSH-related enzymes plays an important role in protecting cells against free radical damage and dictating tumor cell response to adjuvant cancer therapies, including irradiation and chemotherapy. Glutamate cysteine ligase (GCL), glutathione synthetase (GS), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferases (GST), and GSH complex export transporters (GS-X pumps) are major components of the GSH-dependent enzyme system that function in a dynamic cascade to maintain redox homeostasis. In many tumors, the GSH system is often dysregulated, resulting in a more drug resistant phenotype. This is commonly associated with GST-mediated GSH conjugation of various anticancer agents leading to the formation of less toxic GSH–drug complexes, which can be readily exported from the cell. Advances in our understanding of the mechanisms of drug resistance and patient selection based on biomarker profiles will be crucial to adapt therapeutic strategies and improve outcomes for patients with primary malignant brain tumors.
Keywords: Abbreviations; GSH; glutathione; GCL; glutamate cysteine ligase; GS; glutathione synthetase; GPx; glutathione peroxidase; GR; glutathione reductase; GST; glutathione-S-transferase; ROS; reactive oxygen species; Mrp; multidrug resistance-associated protein; γ-GC; γ-glutamylcysteine; GSSG; glutathione disulfide; GCLC; GCL catalytic subunit; GCLM; GCL modulatory subunit; EAAT; excitatory amino acid transporter; BSO; l; -buthionine-S,R-sulfoximine; CPA; cyclophosphamide; γGT; γ-glutamyltranspeptidase; EAAC; excitatory amino acid carrier; X; c; −; glutamate-cystine antiporter; CNS; central nervous system; GBM; glioblastoma multiforme; NAC; N-acetyl cysteine; CPT; camptothecin; CENU; chloroethylnitrosourea; 4-HC; hydroperoxy-CPA; ACNU; nimustine hydrochloride; BCNU; bis-chloroethylnitrosourea; PNET; primitive neuroectodermal tumor; EGF; epidermal growth factor; EGFR; epidermal growth factor receptor; EGFR-TK; epidermal growth factor receptor tyrosine kinaseGlutathione; Brain tumor; Drug resistance
Tumour heterogeneity and drug resistance: Personalising cancer medicine through functional genomics
by Alvin J.X. Lee; Charles Swanton (pp. 1013-1020).
Intrinsic and acquired drug resistance leads to the eventual failure of cancer treatment regimens in the majority of advanced solid tumours. Understanding drug resistance mechanisms will prove vital in the future development of personalised therapeutic approaches. Functional genomics technologies may permit the discovery of predictive biomarkers by unravelling pathways involved in drug resistance and allow the systematic identification of novel therapeutic targets. Such technologies offer the opportunity to develop personalised treatments and diagnostic tools that may improve the survival and quality of life of patients with cancer. However, despite progress in biomarker and drug target discovery, inter-tumour and intra-tumour molecular heterogeneity will limit the effective treatment of this disease. Combining an improved understanding of cancer cell survival mechanisms associated with intra-tumour heterogeneity and drug resistance may allow the selection of patients for specific treatment regimens that will maximise benefit, limit the acquisition of drug resistance and lessen the impact of deleterious side effects.
Keywords: Cancer; Drug resistance; RNA interference; Biomarkers; Chromosomal instability
Nuclear export of proteins and drug resistance in cancer
by Joel G. Turner; Jana Dawson; Daniel M. Sullivan (pp. 1021-1032).
The intracellular location of a protein is crucial to its normal functioning in a cell. Cancer cells utilize the normal processes of nuclear-cytoplasmic transport through the nuclear pore complex of a cell to effectively evade anti-neoplastic mechanisms. CRM1-mediated export is increased in various cancers. Proteins that are exported in cancer include tumor-suppressive proteins such as retinoblastoma, APC, p53, BRAC1, FOXO proteins, INI1/hSNF5, galectin-3, Bok, nucleophosmin, RASSF2, Merlin, p21CIP, p27KIP1, N-WASP/FAK, estradiol receptor and Tob, drug targets topoisomerase I and IIα and BCR-ABL, and the molecular chaperone protein Hsp90. Here, we review in detail the current processes and known structures involved in the export of a protein through the nuclear pore complex. We also discuss the export receptor molecule CRM1 and its binding to the leucine-rich nuclear export signal of the cargo protein and the formation of a nuclear export trimer with RanGTP. The therapeutic potential of various CRM1 inhibitors will be addressed, including leptomycin B, ratjadone, KOS-2464, and specific small molecule inhibitors of CRM1, N-azolylacrylate analogs, FOXO export inhibitors, valtrate, acetoxychavicol acetate, CBS9106, and SINE inhibitors. We will also discuss examples of how drug resistance may be reversed by targeting the exported proteins topoisomerase IIα, BCR-ABL, and galectin-3. As effective and less toxic CRM1 export inhibitors become available, they may be used as both single agents and in combination with current chemotherapeutic drugs. We believe that the future development of low-toxicity, small-molecule CRM1 inhibitors may provide a new approach to treating cancer.
Keywords: CRM1; Drug resistance; Nuclear export signal; Nuclear pore complex; Topoisomerase
NAD(P)H:quinone oxidoreductase 1 (NQO1) in the sensitivity and resistance to antitumor quinones
by David Siegel; Chao Yan; David Ross (pp. 1033-1040).
Quinones represent a large and diverse class of antitumor drugs and many quinones are approved for clinical use or are currently undergoing evaluation in clinical trials. For many quinones reduction to the hydroquinone has been shown to play a key role in their antitumor activity. The two-electron reduction of quinones by NQO1 has been shown to be an efficient pathway to hydroquinone formation. NQO1 is expressed at high levels in many human solid tumors making this enzyme ideally suited for intracellular drug activation. Cellular levels of NQO1 are influenced by the NQO1*2 polymorphism. Individuals homozygous for the NQO1*2 allele are NQO1 null and homozygous NQO1*2*2 cell lines have been shown to be more resistant to antitumor quinones when compared to isogenic cell lines overexpressing NQO1. In this review we will discuss the role of NQO1 in the sensitivity and resistance of human cancers to the quinone antitumor drugs mitomycin C, β-lapachone and the benzoquinone ansamycin class of Hsp90 inhibitors including 17-AAG. The role of NQO1 in the bioreductive activation of mitomycin C remains controversial but pre-clinical data strongly suggests a role for NQO1 in the activation of β-lapachone and the benzoquinone ansamycin class of Hsp90 inhibitors. Despite a large volume of preclinical data demonstrating that NQO1 is an important determinant of sensitivity to these antitumor quinones there is little information on whether the clinical response to these agents is influenced by the NQO1*2 polymorphism. The availability of simple assays for the determination of the NQO1*2 polymorphism should facilitate clinical testing of this hypothesis.
Keywords: Quinone; NQO1; Polymorphism
Acquired resistance to drugs targeting receptor tyrosine kinases
by Steven A. Rosenzweig (pp. 1041-1048).
Development of resistance to chemotherapeutic drugs represents a significant hindrance to the effective treatment of cancer patients. The molecular mechanisms responsible have been investigated for over half a century and have revealed the lack of a single cause. Rather, a multitude of mechanisms have been delineated ranging from induction and expression of membrane transporters that pump drugs out of cells (multidrug resistance (MDR) phenotype), changes in the glutathione system and altered metabolism to name a few. Treatment of cancer patients/cancer cells with chemotherapeutic agents and/or molecularly targeted drugs is accompanied by acquisition of resistance to the treatment administered. Chemotherapeutic agent resistance was initially assumed to be due to induction of mutations leading to a resistant phenotype. This has also been true for molecularly targeted drugs. Considerable experience has been gained from the study of agents targeting the Bcr-Abl tyrosine kinase including imatinib, dasatinib and sunitinib. It is clear that mutations alone are not responsible for the many resistance mechanisms in play. Rather, additional mechanisms are involved, ranging from epigenetic changes, alternative splicing and the induction of alternative/compensatory signaling pathways. In this review, resistance to receptor tyrosine kinase inhibitors (RTKIs), RTK-directed antibodies and antibodies that inactivate ligands for RTKs are discussed. New approaches and concepts aimed at avoiding the generation of drug resistance will be examined. The recent observation that many RTKs, including the IGF-1R, are dependence receptors that induce apoptosis in a ligand-independent manner will be discussed and the implications this signaling paradigm has on therapeutic strategies will be considered.
Keywords: Abbreviations; Akt; Ak (mouse strain) – thymoma; Axl; a receptor tyrosine kinase; Bcr-Abl; breakpoint cluster-Abelson tyrosine kinase; CML; chronic myelogenous Leukemia; CrkL; v-crk sarcoma virus CT10 oncogene homolog (avian)-like; DACH1; Dachshund homolog 1 (Drosophila); Dok; docking protein (downstream of tyrosine kinase 1); DTP; drug-tolerant persisters; DTEP; drug-tolerant expanded persisters; ECD; extracellular domain; EGF; epidermal growth factor; EGFR; epidermal growth factor receptor; Erk; extracellular-regulated kinase; FGFR; fibroblast growth factor receptor; FIT3; FMS-like tyrosine kinase 3; GIST; gastrointestinal stromal tumor; Grb2; growth factor receptor bound-2; HDAC; histone deacetylase; HER2; human epidermal growth factor receptor 2; HGF; hepatocyte growth factor; IGF; insulin-like growth factor; IGF-F1-1; cyclic hexadecapeptide, IGF antagonist; IGF-1R; insulin-like growth factor-1 receptor; IGFBP; insulin-like growth factor binding protein; IQGAP1; Ras GTPase-activating-like protein; Jak; Janus kinase; KD; kinase domain; mAb; monoclonal antibody; MAPK; mitogen-activated protein kinase; MDR; multidrug resistance; MEK; map kinase kinase; Met; MNNG HOS Transforming gene; mTOR; mammalian target of rapamycin; NSCLC; non-small cell lung cancer; OCT1; organic cation transporter 1; PDGFR; platelet-derived growth factor; PDK1; phosphoinositide-dependent kinase 1; PH; pleckstrin homology; PI3K; phosphoinositide 3-kinase; PTB; phosphotyrosine binding domain; PTEN; phosphatase and tensin homolog; Raf; Ras family member; Ras; rat sarcoma; RTK; receptor tyrosine kinase; SH2; src homology 2 domain; Shc; SH2 domain containing; SHIP; SH2 domain-containing inositol phosphatase; Sos; son of sevenless; c-Src; cellular-sarcoma; Stat; signal transducer and activator of transcription; TKI; tyrosine kinase inhibitor; Vav; guanine nucleotide exchange factor, vertical line, pillar (Hebrew); VEGFR; vascular endothelial growth factor receptorReceptor tyrosine kinases; Bcr-Abl; Epidermal growth factor receptor; Dependence receptors
Resistance and gain-of-resistance phenotypes in cancers harboring wild-type p53
by Michelle Martinez-Rivera; Zahid H. Siddik (pp. 1049-1062).
Chemotherapy is the bedrock for the clinical management of cancer, and the tumor suppressor p53 has a central role in this therapeutic modality. This protein facilitates favorable antitumor drug response through a variety of key cellular functions, including cell cycle arrest, senescence, and apoptosis. These functions essentially cease once p53 becomes mutated, as occurs in ∼50% of cancers, and some p53 mutants even exhibit gain-of-function effects, which lead to greater drug resistance. However, it is becoming increasingly evident that resistance is also seen in cancers harboring wild-type p53. In this review, we discuss how wild-type p53 is inactivated to render cells resistant to antitumor drugs. This may occur through various mechanisms, including an increase in proteasomal degradation, defects in post-translational modification, and downstream defects in p53 target genes. We also consider evidence that the resistance seen in wild-type p53 cancers can be substantially greater than that seen in mutant p53 cancers, and this poses a far greater challenge for efforts to design strategies that increase drug response in resistant cancers already primed with wild-type p53. Because the mechanisms contributing to this wild-type p53 “gain-of-resistance” phenotype are largely unknown, a concerted research effort is needed to identify the underlying basis for the occurrence of this phenotype and, in parallel, to explore the possibility that the phenotype may be a product of wild-type p53 gain-of-function effects. Such studies are essential to lay the foundation for a rational therapeutic approach in the treatment of resistant wild-type p53 cancers.
Keywords: Abbreviations; ALL; acute lymphocytic leukemia; APAF-1; apoptotic protease-activating factor 1; AIF; apoptosis-inducing factor; ATM; ataxia telangiectasia mutated; ATR; ataxia telangiectasia and Rad3-related; CBP; cAMP-response element-binding protein-binding protein; Cdk; cyclin-dependent kinase; CLL; chronic lymphocytic leukemia; DAP; 1R; ,; 2R; -diaminocyclohexane(; trans; -diacetato)(dichloro)platinum(IV); DISC; death-inducing signaling complex; DSBs; DNA double-strand breaks; FADD; Fas-associated death domain; 5-FU; 5-fluorouracil; HIPK2; homeodomain-interacting protein kinase 2; HNSCC; head and neck squamous cell carcinoma; HPV-16; human papillomavirus type 16; IC; 50; drug concentration that inhibits cell proliferation by 50%; MEF; mouse embryonic fibroblasts; MRN; Mre11/Rad50/NBS1 complex; NSCLC; non-small cell lung cancer; RCC; renal cell carcinoma; TNF-R; tumor necrosis factor receptorTumor suppressor p53; Antitumor drug response; Drug resistance; Gain-of-function mutants; Gain-of-resistance phenotype; Post-translational modifications
Regulation of chemoresistance via alternative messenger RNA splicing
by Scott T. Eblen (pp. 1063-1072).
The acquisition of resistance to chemotherapy is a significant problem in the treatment of cancer, greatly increasing patient morbidity and mortality. Tumors are often sensitive to chemotherapy upon initial treatment, but repeated treatments can select for those cells that were able to survive initial therapy and have acquired cellular mechanisms to enhance their resistance to subsequent chemotherapy treatment. Many cellular mechanisms of drug resistance have been identified, most of which result from changes in gene and protein expression. While changes at the transcriptional level have been duly noted, it is primarily the post-transcriptional processing of pre-mRNA into mature mRNA that regulates the composition of the proteome and it is the proteome that actually regulates the cell's response to chemotherapeutic insult, inducing cell survival or death. During pre-mRNA processing, intronic non-protein-coding sequences are removed and protein-coding exons are spliced to form a continuous template for protein translation. Alternative splicing involves the differential inclusion or exclusion of exonic sequences into the mature transcript, generating different mRNA templates for protein production. This regulatory mechanism enables the potential to produce many different protein isoforms from the same gene. In this review I will explain the mechanism of alternative pre-mRNA splicing and look at some specific examples of how splicing factors, splicing factor kinases and alternative splicing of specific pre-mRNAs from genes have been shown to contribute to acquisition of the drug resistant phenotype.
Keywords: Alternative splicing; Drug resistance; Spliceosome; Cyclin D1; c-FLIP
ABC transporters and their role in nucleoside and nucleotide drug resistance
by Yu Fukuda; John D. Schuetz (pp. 1073-1083).
ATP-binding cassette (ABC) transporters confer drug resistance against a wide range of chemotherapeutic agents, including nucleoside and nucleotide based drugs. While nucleoside based drugs have been used for many years in the treatment of solid and hematological malignancies as well as viral and autoimmune diseases, the potential contribution of ABC transporters has only recently been recognized. This neglect is likely because activation of nucleoside derivatives require an initial carrier-mediated uptake step followed by phosphorylation by nucleoside kinases, and defects in uptake or kinase activation were considered the primary mechanisms of nucleoside drug resistance. However, recent studies demonstrate that members of the ABCC transporter subfamily reduce the intracellular concentration of monophosphorylated nucleoside drugs. In addition to the ABCC subfamily members, ABCG2 has been shown to transport nucleoside drugs and nucleoside-monophosphate derivatives of clinically relevant nucleoside drugs such as cytarabine, cladribine, and clofarabine to name a few. This review will discuss ABC transporters and how they interact with other processes affecting the efficacy of nucleoside based drugs.
Keywords: ABC transporter; Nucleoside drug; Drug resistance; Nucleoside kinase; Cancer
Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance
by Karthika Natarajan; Yi Xie; Maria R. Baer; Douglas D. Ross (pp. 1084-1103).
Since cloning of the ATP-binding cassette (ABC) family member breast cancer resistance protein (BCRP/ABCG2) and its characterization as a multidrug resistance efflux transporter in 1998, BCRP has been the subject of more than two thousand scholarly articles. In normal tissues, BCRP functions as a defense mechanism against toxins and xenobiotics, with expression in the gut, bile canaliculi, placenta, blood-testis and blood-brain barriers facilitating excretion and limiting absorption of potentially toxic substrate molecules, including many cancer chemotherapeutic drugs. BCRP also plays a key role in heme and folate homeostasis, which may help normal cells survive under conditions of hypoxia. BCRP expression appears to be a characteristic of certain normal tissue stem cells termed “side population cells,” which are identified on flow cytometric analysis by their ability to exclude Hoechst 33342, a BCRP substrate fluorescent dye. Hence, BCRP expression may contribute to the natural resistance and longevity of these normal stem cells. Malignant tissues can exploit the properties of BCRP to survive hypoxia and to evade exposure to chemotherapeutic drugs. Evidence is mounting that many cancers display subpopulations of stem cells that are responsible for tumor self-renewal. Such stem cells frequently manifest the “side population” phenotype characterized by expression of BCRP and other ABC transporters. Along with other factors, these transporters may contribute to the inherent resistance of these neoplasms and their failure to be cured.
Keywords: ATP binding cassette transporters; Breast cancer resistance protein; ABCG2; Drug absorption, distribution, metabolism and excretion; Cancer; Drug resistance
Nanoparticle-based combination therapy toward overcoming drug resistance in cancer
by Che-Ming Jack Hu; Liangfang Zhang (pp. 1104-1111).
The use of multiple therapeutic agents in combination has become the primary strategy to treat drug resistant cancers. However, administration of combinatorial regimens is limited by the varying pharmacokinetics of different drugs, which results in inconsistent drug uptake and suboptimal drug combination at the tumor sites. Conventional combination strategies in aim to maximize therapeutic efficacy based on maximum tolerated dose does not account for the therapeutic synergism that is sensitive to both dosing and scheduling of multiple drugs. In the present review, we will discuss the development of multidrug-loaded nanoparticles against drug resistant cancers. Nanoparticle-based combination therapy against experimental multidrug resistant (MDR) cancer models will be summarized. In addition, we will highlight the recent advances in nanoparticle-based combination strategies against clinical cancer drug resistance, including co-encapsulation of drugs with different physicochemical properties, ratiometric control over drug loading, and temporal sequencing on drug release. These emerging strategies promise novel and better tailored combinatorial regimens for clinical cancer treatment.
Keywords: Multidrug resistance; Combination therapy; Therapeutic synergism; Nanoparticle drug delivery; Cancer treatment
Nuclear receptors in the multidrug resistance through the regulation of drug-metabolizing enzymes and drug transporters
by Yakun Chen; Yong Tang; Changxiong Guo; Jiuhui Wang; Debasish Boral; Daotai Nie (pp. 1112-1126).
Chemotherapy is one of the three most common treatment modalities for cancer. However, its efficacy is limited by multidrug resistant cancer cells. Drug metabolizing enzymes (DMEs) and efflux transporters promote the metabolism, elimination, and detoxification of chemotherapeutic agents. Consequently, elevated levels of DMEs and efflux transporters reduce the therapeutic effectiveness of chemotherapeutics and, often, lead to treatment failure. Nuclear receptors, especially pregnane X receptor (PXR, NR1I2) and constitutive androstane activated receptor (CAR, NR1I3), are increasingly recognized for their role in xenobiotic metabolism and clearance as well as their role in the development of multidrug resistance (MDR) during chemotherapy. Promiscuous xenobiotic receptors, including PXR and CAR, govern the inducible expressions of a broad spectrum of target genes that encode phase I DMEs, phase II DMEs, and efflux transporters. Recent studies conducted by a number of groups, including ours, have revealed that PXR and CAR play pivotal roles in the development of MDR in various human carcinomas, including prostate, colon, ovarian, and esophageal squamous cell carcinomas. Accordingly, PXR/CAR expression levels and/or activation statuses may predict prognosis and identify the risk of drug resistance in patients subjected to chemotherapy. Further, PXR/CAR antagonists, when used in combination with existing chemotherapeutics that activate PXR/CAR, are feasible and promising options that could be utilized to overcome or, at least, attenuate MDR in cancer cells.
Keywords: Abbreviations; ABC; ATP binding cassette; AF; activation function; AhR; aryl hydrocarbon receptor; AHRE; AhR element; AIP; aryl hydrocarbon receptor-interacting protein; AKRs; aldo–keto reductases; ARE; antioxidant response element; ARNT; aryl hydrocarbon receptor nuclear translocator; BSEP; bile salt export pump; CAR; constitutive androstane receptor; CCRP; cytoplasmic CAR retention protein; CRE; CREB response element; CYP; cytochrome P450; DBD; DNA-binding domain; DEX; dexamethasone; DMEs; drug metabolizing enzymes; DRE; dioxin-responsive element; EPHs; epoxide hydrolases; ER; endoplasmic reticulum; FXR; farnesoid X receptor; FXRE; FXR response element; GR; glucocorticoid receptor; GSTs; glutathione S-transferases; HREs; hormone response elements; HSP90; 90-kDa heat shock protein; IABP; intra-aortic balloon pump; LBD; ligand binding domain; LBP; ligand binding pocket; LXR; liver X receptor; LXRE; LXR response element; MDR; multidrug resistance; MRP; multidrug resistance-associated protein; NATs; N-acetyltransferases; NCoR; nuclear receptor corepressor; NLS; nuclear localization sequence; NMO; NAD(P)H:menadione reductase; OATPs; organic anion-transporting polypeptides; OCTs; organic cation transporters; P-gp; P-glycoprotein; PB; phenobarbital; PBP/PPARBP; PPAR-binding protein; PCAF; P300/CBP-associated factor; PCN; pregnenolone 16-alpha carbonitrile; PLTP; phospholipid transfer protein; PPAR; peroxisome proliferator activated receptor; PPRE; peroxisome proliferator response element; PXR; pregnane X receptor; QR; quinone reductase; RAREs; retinoic acid response elements; RXR; retinoid X receptor; SJW; St. John's Wort; SMRT; silencing mediator for retinoid and thyroid hormone receptor; SRCs; steroid receptor co-activators; SULTs; sulfotransferases; TCPOBOP; 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene; TIF2; transcriptional mediators/intermediary factor 2; TPR; tetratricopeptide repeat; UGTs; UDP-glucuronosyltranferases; XO; xanthine oxidase; XRE; xenobiotic response elementMultidrug resistance; PXR; CAR; AHR; DME
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