Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism of action of chemotherapeutic drugs and their ability to induce multidrug resistance (MDR) are of relevance to cancer treatment. Overexpression of P-glycoprotein (Pgp) encoded by the MDR1 gene following chemotherapy can severely limit the efficacy of anticancer agents; however, the manner by which cells acquire high levels of Pgp has not been defined. Herein, we demonstrate that chemotherapeutic drugs induce specific epigenetic modifications at the MDR1 locus, concomitant with MDR1 upregulation mediated by transcriptional activation, and a potential post-transcriptional component. We have established that the mechanisms are not mutually exclusive and are dependent on the methylation state of the MDR1 promoter. MDR1 upregulation did not result in further changes to the CpG methylation profile. However, dramatic changes in the temporal and spatial patterning of histone modifications occurred within the 5' hypomethylated region of MDR1, directly correlating with MDR1 upregulation. Specifically, drug-induced upregulation of MDR1 was associated with increases in H3 acetylation and induction of methylated H3K4 within discrete regions of the MDR1 locus. Our results demonstrate that chemotherapeutic drugs can actively induce epigenetic changes within the MDR1 promoter, and enhance the MDR phenotype.
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PMID:Epigenetic changes to the MDR1 locus in response to chemotherapeutic drugs. 1609 41

The multidrug resistance 1 (MDR1) gene product P-glycoprotein (P-gp) is frequently implicated in cross-resistance of tumors to chemotherapeutic drugs. In contrast, acute promyelocytic leukemia (APL) cells do not express MDR1 and are highly sensitive to anthracyclines. The combination of ATRA and the novel histone deacetylase inhibitor (HDACI) depsipeptide (FK228) induced P-gp expression and prevented growth inhibition and apoptosis in NB4 APL cells subsequently exposed to doxorubicin (DOX). ATRA/FK228 treatment after exposure to DOX, however, enhanced apoptosis. Both agents, ATRA or FK228, induced MDR1 mRNA. This effect was significantly enhanced by ATRA/FK228 administered in combination, due in part to increased H4 and H3-Lys9 acetylation of the MDR1 promoter and recruitment of the nuclear transcription factor Y alpha (NFYA) transcription activator to the CCAAT box. Cotreatment with specific P-gp inhibitor PSC833 reversed cytoprotective effects of ATRA/FK228. G1 cell-cycle arrest and p21 mRNA induction were also observed in response to ATRA/FK228, which may restrict DOX-induced apoptosis of cells in G2 phase. These results indicate that epigenetic mechanisms involving NF-YA transcription factor recruitment and histone acetylation are activated by ATRA and HDACI, induce MDR1 in APL cells, and point to the critical importance of mechanism-based sequential therapy in future clinical trials that combine HDAC inhibitors, ATRA, and anthracyclines.
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PMID:Up-regulation of MDR1 and induction of doxorubicin resistance by histone deacetylase inhibitor depsipeptide (FK228) and ATRA in acute promyelocytic leukemia cells. 1622 81

Taxanes are important drugs in the treatment of ovarian and other cancers, but their efficacy is limited by intrinsic and acquired drug resistance. Expression of the multidrug transporter P-glycoprotein, encoded by the MDR1 (ABCB1) gene, is one of the causes of clinical drug resistance to taxanes. To study the mechanisms of MDR1 activation related to taxanes, we established 11 multidrug-resistant variants from six ovarian cancer cell lines by continuous exposure to either paclitaxel or docetaxel. We profiled gene expression and gene copy number alterations in these cell lines using cDNA microarrays and identified a cluster of genes coactivated with MDR1 in 7q21.11-13. Regional activation was evident in nine resistant variants displaying a coexpression pattern of up to 22 genes over an 8-Mb area, including SRI, MGC4175, CLDN12, CROT, and CDK6. In six of these variants, regional activation was driven by gene copy number alterations, with low-level gains or high-level amplifications spanning the involved region. However, three variants displayed regional increases in gene expression even without concomitant gene copy number changes. These results suggest that regional gene activation may be a fundamental mechanism for acquired drug resistance, with or without changes in gene dosage. In addition to numerical and structural chromosomal changes driven by genome instability in cancer cells, other mechanisms might be involved in MDR1 regional activation, such as chromatin remodeling and DNA or histone modifications of the 7q21 region.
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PMID:Regional activation of chromosomal arm 7q with and without gene amplification in taxane-selected human ovarian cancer cell lines. 1638 45

Histone deacetylase (HDAC) inhibitors are considered to be drugs for targeted cancer therapy and second-generation HDIs are currently being tested in clinical trials. Here, we report on the synthesis and biological evaluation of a novel HDAC inhibitor scaffold with the hydroxamate Zn(2+) complexing headgroup, selected from the 2-aroylindol motif. Inhibition of nuclear extract HDAC and recombinant HDAC 1 as well as induction of histone H3K(9+14) hyperacetylation mediated by E-N-hydroxy-(2-aroylindole)acrylamides or E-N-hydroxy-(2-aroylbenzofuran)acrylamides were studied. Moreover, the cytotoxic activity, the effects on the cell cycle, and histone H3S(10) phosphorylation of selected compounds were determined. By use of a panel of 24 different human tumor cell lines, mean IC(50) values of the most potent analogues 6c and 7b were 0.75 and 0.65 microM, respectively. The novel compounds were shown to be no substrates of the P-glycoprotein drug transporter. Comparable to N(1)-hydroxy-N(8)-phenyloctanediamide "2 (SAHA)", cells in the S phase of the cell cycle are depleted, with partial arrest in G1 and G2/M and finally induction of massive apoptosis.
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PMID:2-aroylindoles and 2-aroylbenzofurans with N-hydroxyacrylamide substructures as a novel series of rationally designed histone deacetylase inhibitors. 1769 63

Resistance to the cytotoxic actions of antineoplastic drugs remains a barrier to the establishment of curative chemotherapy regimens for cancer. Over-expression of P-glycoprotein (P-gp), encoded by the MDR1 gene is the major molecular mechanism enhancing efflux pump for various anticancer agents, hence caused MDR. Transcription factor, DNA methylation, histone acetylation/deacetylation, phosphorylation and glycosylation and MDR1 gene polymorphisms play pivotal role in regulation of P-glycoprotein, and may become new therapeutic targets. This paper summarized the advances of studies on expression and regulation of P-glycoprotein.
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PMID:[Advances in the study of expression and regulation of P-glycoprotein]. 1805 Jul 30

Camptothecin (CPT) analogues are powerful anticancer agents but are chemically unstable due to their alpha-hydroxylactone six-membered E-ring structure, which is essential for trapping topoisomerase I (Top1)-DNA cleavage complexes. To stabilize the E-ring, CPT keto analogues with a five-membered E-ring lacking the oxygen of the lactone ring (S38809 and S39625) have been synthesized. S39625 has been selected for advanced preclinical development based on its promising activity in tumor models. Here, we show that both keto analogues are active against purified Top1 and selective against Top1 in yeast and human cancer cells. The keto analogues show improved cytotoxicity toward colon, breast, and prostate cancer cells and leukemia cells compared with CPT. The drug-induced Top1-DNA cleavage complexes induced by the keto analogues show remarkable persistence both with purified Top1 and in cells following 1-h drug treatments. Moreover, we find that S39625 is not a substrate for either the ABCB1 (multidrug resistance-1/P-glycoprotein) or ABCG2 (mitoxantrone resistance/breast cancer resistance protein) drug efflux transporters, which sets S39625 apart from the clinically used CPT analogues topotecan or SN-38 (active metabolite of irinotecan). Finally, we show that nanomolar concentrations of S38809 or S39625 induce intense and persistent histone gamma-H2AX. The chemical stability of the keto analogues and the ability of S39625 to produce high levels of persistent Top1-DNA cleavage complex and its potent antiproliferative activity against human cancer cell lines make S39625 a promising new anticancer drug candidate. Histone gamma-H2AX could be used as a biomarker for the upcoming clinical trials of S39625.
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PMID:Novel E-ring camptothecin keto analogues (S38809 and S39625) are stable, potent, and selective topoisomerase I inhibitors without being substrates of drug efflux transporters. 1808 16

Oral bioavailability is one of the important criteria for development of a drug-lead candidate. In this study, the absorptive characteristics and the efflux mechanism of a mercaptoacetamide-based histone deacetyalse (HDAC) inhibitor, coded as W2, were investigated using Caco-2 cells. The transport of W2 was asymmetric as indicated by 1.85 fold higher basolateral to apical (BL to AP) than apical to basolateral (AP to BL) flux. Such asymmetry was associated with multidrug resistance associated protein 1 (MRP1) and P-glycoprotein (P-gp), as evidenced by specific inhibition of these proteins. In the presence of verapamil and cyclosporin A, potent inhibitors of P-gp, the apparent permeability ratio (P(app) BL to AP/P(app) AP to BL) of W2 was decreased from 1.85 to 0.73 and 1.03, respectively, and the absorption from apical to basolateral side was enhanced from 13.3+/-0.2x10(-6) cm/s to 17.3+/-0.12x10(-6) cm/s and 19+/-0.3x10(-6) cm/s, respectively. Upon addition of quinidine, a mixed P-gp and MRP1 inhibitor, the permeation of W2 from the apical side was significantly increased (P(app) 17.1+/-0.32x10(-6) cm/s) while the efflux was inhibited (P(app) 21.3+/-0.19x10(-6) cm/s). Furthermore, the influence of the MRP1 inhibitors, indomethacin and N-benzyl-indomethacin (NBI) was evaluated. NBI treatment attenuated the basolateral to apical flux of W2 (P(app) 20.3+/-0.1x10(-6) cm/s), whereas this effect was completely abrogated by indomethacin (P(app) 11+/-0.4x10(-6) cm/s). The results suggest that P-gp and MRP1 transporters are capable of mediating the efflux of W2 and might play a significant role in its oral absorption.
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PMID:Involvement of P-glycoprotein and multidrug resistance associated protein 1 on the transepithelial transport of a mercaptoacetamide-based histone-deacetylase inhibitor in Caco-2 cells. 1912 84

Overexpression of MDR1 in breast cancer remains a major cause for the failure of chemotherapy. In the present report, we find UHRF1 plays an important role in inhibiting MDR1 promoter activity by directly binding to the MDR1 promoter. Knockdown of UHRF1 activates MDR1 promoter activity and expression, attenuates the binding of UHRF1 and HDAC1 to the MDR1 promoter.Overexpression of UHRF1 in NCI/ADR-RES cells can induce deacetylation of histones H3 and H4 on the MDR1 promoter, which is facilitated by recruitment of HDAC1 to the MDR1 promoter. Loss of histone acetylation is accompanied by loss of binding of the key transcription factor, MyoD, CBP and p300, locking in marked suppression of MDR1, increasing sensitivity of MDR cancer cells to cytotoxic drugs that are transported by P-glycoprotein(P-gp). The inhibition of MDR1 expression by UHRF1 may provide potential ways to overcome multidrug resistance (MDR) in breast cancer treatment.
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PMID:UHRF1 inhibits MDR1 gene transcription and sensitizes breast cancer cells to anticancer drugs. 2003 78

The orphan nuclear receptor pregnane X receptor regulates enzymes and transport proteins involved in the detoxification and clearance of numerous endobiotic and xenobiotic compounds, including pharmaceutical agents. Multiple alternatively spliced pregnane X receptor isoforms have been identified which are significantly expressed in humans and mice (up to 30% of the total pregnane X receptor transcript), however, little is known about their biological action. We explored functional differences between the major mouse pregnane X receptor isoforms mPXR(431) and mPXR(Delta171-211) that lacks 41 amino acids adjacent to the ligand-binding pocket. Transient transfection assays showed that mPXR(Delta171-211) reduced the basal transcription of cytochrome P450 3A4 and the drug transporter P-glycoprotein/Multi Drug Resistance Protein 1 and directly repressed the regulatory effects of mPXR(431) on these genes. Replacement of the mPXR(Delta171-211) DNA-binding domain with that of GAL4 showed mPXR(Delta171-211) retained its repressive role independent of binding to PXR responsive elements located within the cytochrome P450 3A4 and Multi Drug Resistance Protein 1 regulatory regions. Use of the histone deacetylase inhibitor, trichostatin A, demonstrated that the repressive function of mPXR(Delta171-211) acts independently of histone acetylation state. Protein interaction assays revealed mPXR(Delta171-211) and mPXR(431) differentially bind the obligatory heterodimer partner retinoid X receptor. Furthermore, mPXR(431) and mPXR(Delta171-211) proteins could heterodimerize. These studies demonstrate that the variant mouse PXR isoform, mPXR(Delta171-211), has a distinct repressive function from mPXR(431) in regulating genes encoding important drug metabolizing enzymes and transport proteins.
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PMID:The alternatively spliced murine pregnane X receptor isoform, mPXR(delta171-211) exhibits a repressive action. 2006 Sep 28

The multidrug resistance 1 gene (MDR1) encodes P-glycoprotein (Pgp), a member of the ATP-binding cassette (ABC) transporter family that confers tumor drug resistance by actively effluxing a number of antitumor agents. We had previously shown that MDR1 transcription is regulated by epigenetic events such as histone acetylation, and had identified the histone acetylase P/CAF and the transcription factor NF-Y as the factors mediating the enzymatic and DNA-anchoring functions, respectively, at the MDR1 promoter. It has also been shown that MDR1 activation is accompanied by increased methylation on lysine 4 of histone H3 (H3K4). In this study, we further investigated histone methylation in MDR1 regulation and function. We show that the mixed lineage leukemia 1 (MLL1) protein, a histone methyltransferase specific for H3K4, is required for MDR1 promoter methylation, as knockdown of MLL1 resulted in a decrease in MDR1 expression. The regulation of MDR1 by MLL1 has functional consequences in that downregulation of MLL1 led to increased retention of the Pgp-specific substrate DIOC(2)(3), as well as increased cellular sensitivity to several Pgp substrates. Regulation of MDR1 by MLL1 was dependent on the CCAAT box within the proximal MDR1 promoter, similar to what we had shown for MDR1 promoter acetylation, and also requires NF-Y. Finally, overexpression of the most prevalent MLL fusion protein, MLL-AF4, led to increased MDR1 expression. This is the first identification of a histone methyltransferase and its leukemogenic rearrangement that regulates expression of an ABC drug transporter, suggesting a new target for circumvention of tumor multidrug resistance.
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PMID:Histone methyltransferase MLL1 regulates MDR1 transcription and chemoresistance. 2086 Nov 84


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