Multidrug Resistance Proteins (MRPs) and Cancer Therapy

Zhang, Yun-Kai; Wang, Yijun; Gupta, Pranav; Chen, Zhe‐Sheng

doi:10.1208/s12248-015-9757-1

Cited by 155 publications

(112 citation statements)

References 91 publications

(105 reference statements)

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“…Therefore, with the elucidation of the MDR mechanism, MDR has been associated with an adenosine triphosphate (ATP)-dependent decrease in cellular drug accumulation, which is attributed to the overexpression of certain ATP-binding cassette (ABC) transporter proteins (23). There are 9 human MDR proteins that are generally members of subfamily C in the ABC superfamily (23).…”

Section: Reversing Multidrug Resistancementioning

confidence: 99%

Efficacy of traditional Chinese medicine in treating cancer

et al. 2015

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Section: Reversing Multidrug Resistancementioning

confidence: 99%

Efficacy of traditional Chinese medicine in treating cancer

et al. 2015

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“…Over the years, a number of intrinsic and extrinsic cellular mechanisms have been identified and reported to cause MDR in cancer cells, some of which include, alteration in cyclin-dependent kinases (CDKs), regulation of apoptosis, autophagy, and increased DNA repair mechanisms [3-6]. However, the ABC transporters-mediated efflux of chemotherapeutic drugs is the most prominent factor leading to the development of MDR [7, 8].…”

Section: Introductionmentioning

confidence: 99%

Voruciclib, a Potent CDK4/6 Inhibitor, Antagonizes ABCB1 and ABCG2-Mediated Multi-Drug Resistance in Cancer Cells

Gupta

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: The overexpression of ATP-Binding Cassette (ABC) transporters has known to be one of the major obstacles impeding the success of chemotherapy in drug resistant cancers. In this study, we evaluated voruciclib, a CDK 4/6 inhibitor, for its chemo-sensitizing activity in ABCB1- and ABCG2- overexpressing cells. Methods: Cytotoxicity and reversal effect of voruciclib was determined by MTT assay. The intracellular accumulation and efflux of ABCB1 and ABCG2 substrates were measured by scintillation counter. The effects on expression and intracellular localization of ABCB1 and ABCG2 proteins were determined by Western blotting and immunofluorescence, respectively. Vanadate-sensitive ATPase assay was done to determine the effect of voruciclib on the ATPase activity of ABCB1 and ABCG2. Flow cytometric analysis was done to determine the effect of voruciclib on apoptosis of ABCB1 and ABCG2-overexpressing cells and docking analysis was done to determine the interaction of voruciclib with ABCB1 and ACBG2 protein. Results: Voruciclib significantly potentiated the effect of paclitaxel and doxorubicin in ABCB1-overexpressing cells, as well as mitoxantrone and SN-38 in ABCG2-overexpressing cells. Voruciclib moderately sensitized ABCC10- overexpressing cells to paclitaxel, whereas it did not alter the cytotoxicity of substrates of ABCC1. Furthermore, voruciclib increased the intracellular accumulation and decreased the efflux of substrate anti-cancer drugs from ABCB1- or ABCG2-overexpressing cells. However, voruciclib did not alter the expression or the sub-cellular localization of ABCB1 or ABCG2. Voruciclib stimulated the ATPase activity of both ABCB1 and ABCG2 in a concentration-dependent manner. Lastly, voruciclib exhibited a drug-induced apoptotic effect in ABCB1- or ABCG2- overexpressing cells. Conclusion: Voruciclib is currently a phase I clinical trial drug. Our findings strongly support its potential use in combination with conventional anti-cancer drugs for cancer chemotherapy.

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“…4,5 Several chemotherapeutics can be served as substrates for MRPs. 6,7 The antitumor agent doxorubicin (DOX) is widely used for the treatment of various solid tumors via interacting with DNA through intercalation and inhibiting topoisomerase II, but it is also a substrate for MRPs. 8 The abnormal increase of drug efflux and reduced intracellular drug concentration lead to DOX resistance.…”

Section: Introductionmentioning

confidence: 99%

Doxorubicin-loaded redox-responsive micelles based on dextran and indomethacin for resistant breast cancer

Zhou¹,

Wang²,

Ying³

et al. 2017

IJN

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Multidrug resistance (MDR) against chemotherapeutic agents has become one of the major obstacles to successful cancer therapy and MDR-associated proteins (MRPs)-mediated drug efflux is the key factor for MDR. In this study, a redox-responsive polymer based on dextran (DEX) and indomethacin (IND), which could reduce MRPs-mediated efflux of chemotherapeutics, was synthesized, and the obtained polymer could spontaneously form stable micelles with well-defined core-shell structure and a uniform size distribution with an average diameter of 50 nm and effectively encapsulate doxorubicin (DOX); the micelles contain a disulfide bridge (cystamine, SS) between IND and DEX (DEX-SS-IND). In vitro drug release results indicated that DEX-SS-IND/DOX micelles could maintain good stability in a stimulated normal physiological environment and promptly depolymerized and released DOX in a reducing environment. After incubating DEX-SS-IND/DOX micelles with drug-resistant tumor (MCF-7/ADR) cells, the intracellular accumulation and retention of DOX were significantly increased under the synergistic effects of redox-responsive delivery and the inhibitory effect of IND on MRPs. In vitro cytotoxicity showed that DEX-SS-IND/DOX micelles exhibited higher cytotoxicity against MCF-7/ADR cells. Moreover, DEX-SS-IND/DOX micelles showed significantly enhanced inhibition of tumor in BALB/c nude mice bearing MCF-7/ADR tumors and reduced systemic toxicity. Overall, the cumulative evidence indicates that DEX-SS-IND/DOX micelles hold significant promise for overcoming MDR for cancer therapy.

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Multidrug Resistance Proteins (MRPs) and Cancer Therapy

Cited by 155 publications

References 91 publications

Efficacy of traditional Chinese medicine in treating cancer

Efficacy of traditional Chinese medicine in treating cancer

Voruciclib, a Potent CDK4/6 Inhibitor, Antagonizes ABCB1 and ABCG2-Mediated Multi-Drug Resistance in Cancer Cells

Doxorubicin-loaded redox-responsive micelles based on dextran and indomethacin for resistant breast cancer

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