The molecular basis of multidrug resistance in cancer: The early years of P‐glycoprotein research

Gottesman, Michael M.; Ling, Victor

doi:10.1016/j.febslet.2005.12.060

Cited by 490 publications

(349 citation statements)

References 70 publications

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“…One of the common forms of resistance to chemotherapy is caused by activation of the MDR1 (ABCB1) gene, resulting in overexpression of P-glyco-protein (P-gp), a 170-190 kDa transmembrane glycoprotein that belongs to the ATP-binding cassette superfamily and acts as a multidrug transporter [1]. Overexpression of P-gp confers cancer cell resistance to a broad range of structurally and functionally diverse chemotherapeutic drugs [2].…”

Section: Introductionmentioning

confidence: 99%

Role of MicroRNA miR-27a and miR-451 in the regulation of MDR1/P-glycoprotein expression in human cancer cells

Zhu

Liu

et al. 2008

Biochemical Pharmacology

420

294

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MicroRNAs are short non-coding RNA molecules able to affect stability and/or translation of mRNA, thereby regulating the expression of genes involved in many biological processes. We report here that microRNAs miR-27a and miR-451 are involved in activating the expression of P-glycoprotein, the MDR1 gene product that confers cancer cell resistance to a broad range of chemotherapeutics. We showed that expressions of miR-27a and miR-451 were up-regulated in multidrug resistant (MDR) cancer cell lines A2780DX5 and KB-V1, as compared with their parental lines A2780 and KB-3-1. Treatment of A2780DX5 cells with the antagomirs of miR-27a or miR-451 decreased the expression of P-glycoprotein and MDR1 mRNA. In contrast, the mimics of miR-27a and miR-451 increased MDR1 expression in the parental cells A2780. The sensitivity to and intracellular accumulation of cytotoxic drugs that are transported by P-glycoprotein were enhanced by the treatment with the antagomirs of miR-27a or miR-451. Our results demonstrate for the first time the roles of microRNAs in the regulation of drug resistance mediated by MDR1/P-glycoprotein, and suggest the potential for targeting miR-27a and miR-451 as a therapeutic strategy for modulating MDR in cancer cells.

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Section: Introductionmentioning

confidence: 99%

Role of MicroRNA miR-27a and miR-451 in the regulation of MDR1/P-glycoprotein expression in human cancer cells

Zhu

Liu

et al. 2008

Biochemical Pharmacology

420

294

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“…P-gp is a 170 ~ 190 kDa transmembrane phospho-glycoprotein that belongs to the ATP-binding cassette superfamily. The ability of P-gp to transport many structurally and functionally diverse cytotoxic compounds such as palitaxel, doxorubicin and vinblastine results in lowered intracellular drug concentration and decreased drug efficacy (1). Multidrug resistance (MDR) mediated by the overexpression of P-gp can be intrinsic, or induced by a variety of chemical or physical insults such as cytotoxic agents, arsenite, heat shock, and UV irradiation (2)(3)(4)(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Involvement of CtBP1 in the transcriptional activation of the MDR1 gene in human multidrug resistant cancer cells

Jin

Scotto

Hait

et al. 2007

Biochemical Pharmacology

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Drug resistance caused by overexpression of P-glycoprotein (P-gp), the MDR1 (ABCB1) gene product, limits the therapeutic outcome. Expression of MDR1 can be induced by divergent stimuli, and involves a number of transcriptional factors. We found that the expression of CtBP1 (C-terminalbinding protein 1), a transcriptional co-regulator, was increased (~4 -fold) in human multidrug resistant (MDR) cancer cell lines, NCI/ADR-RES and A2780/DX, as compared to their sensitive counterparts. Silencing of CtBP1 expression by RNAi decreased the MDR1 mRNA and P-gp. Knockdown of CtBP1 also enhanced the sensitivity of MDR cells to chemotherapeutic drugs that are transported by P-gp and increased intracellular drug accumulation. In a reporter gene assay, cotransfection of MDR1 promoter constructs with a CtBP1 expression vector resulted in a ~2-4-fold induction of MDR1 promoter activity. CtBP1 appeared to contribute to the activation of MDR1 transcription through directly interacting with the MDR1 promoter, as evidenced by its physical binding to the promoter region of the MDR1 gene in chromatin immunoprecipitation and electromobility shift assays. Histone modifications at the MDR1 promoter, such as monomethylation, di-methylation, and acetylation of histone H3, were not found to be affected by silencing of CtBP1 expression. Our results reveal a novel role for CtBP1 as an activator of MDR1 gene transcription, and suggest that CtBP1 might be one of the key transcription factors involved in the induction of MDR1 gene. Therefore, CtBP1 may represent a potentially new target for inhibiting drug resistance mediated by overexpression of the MDR1 gene.

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“…Development of adjuvant agents to circumvent MDR becomes a new trend in cancer chemotherapy. Many attempts, such as inhibition of MDR-related genes, to overcome MDR have been proposed [21] . Inhibition of MDR1 gene function, either by blocking P-gp function or inhibiting MDR1 gene expression, has been one of the most extensive studies [22,23] .…”

Section: Disscussionmentioning

confidence: 99%

Cytotoxicity and reversal of multidrug resistance by tryptanthrin-derived indoloquinazolines

Yu¹,

Chern²,

Chen

et al. 2010

Acta Pharmacol Sin

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Aim: To evaluate the effects and elucidate the mechanisms of a series of indoloquinazolines as novel anticancer agents. Methods: Condensation of the substituted isatoic anhydride with the substituted isatin was performed to prepare compounds 1-4, followed by adding malononitrile to prepare compounds 5-7. Cytotoxicity was measured by MTT assays. Apoptosis induction was evaluated using DNA fragmentation, cell cycle assay, caspase 3/7 activity and Western blot. Results: Compounds 3, 4, and 5 display cytotoxicity against MCF-7, HeLa, SKOV3, and A498 cancer cells. DNA ladders appear in cells treated with compounds 3, 4, and 5. Within those, compound 4 exhibits the greatest activity in regards to sub-G 1 accumulations in the cell cycle and the activation of caspase-3/7. Furthermore, Fas and Fas ligand levels are elevated by compound 4, implying that the apoptosis is in part mediated through the signals. On the other hand, compounds 1 and 7 display chemosensitizing activity since cytotoxicity of doxorubicine and etoposide is enhanced in combination with compound 1 and 7, respectively, in MCF-7/adr (doxorubicinresistant) and MCF-7/vp (etoposide-resistant). Conclusion: The cytotoxicity of indoloquinazolines is structure-dependent rather than cell type-dependent due to the similar degree of cytotoxicity induced by the individual compounds in all four cell lines. Further modification of the tryptanthrin skeleton is important to develop novel anticancer agents bearing either cytotoxicity against MCF-7 cells or drug resistance reversal in MCF-7/adr and MCF-7/ vp.

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The molecular basis of multidrug resistance in cancer: The early years of P‐glycoprotein research

Cited by 490 publications

References 70 publications

Role of MicroRNA miR-27a and miR-451 in the regulation of MDR1/P-glycoprotein expression in human cancer cells

Role of MicroRNA miR-27a and miR-451 in the regulation of MDR1/P-glycoprotein expression in human cancer cells

Involvement of CtBP1 in the transcriptional activation of the MDR1 gene in human multidrug resistant cancer cells

Cytotoxicity and reversal of multidrug resistance by tryptanthrin-derived indoloquinazolines

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