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Multidrug resistance associated proteins in multidrug resistance

Chinese Journal of Cancer 2012年第2期31卷 58-72页

作者： kamlesh sodani Atish Patel Rishil J.Kathawala Department of Pharmaceutical Sciences College of Pharmacy and Allied Health ProfessionsSt.John's UniversityQueensNY 11439USA

Multidrug resistance proteins(MRPs) are members of the C family of a group of proteins named ATP-binding cassette(ABC) *** ABC transporters together form the largest branch of proteins within the human *** MRP family comprises of 13 members,of which MRP1 to MRP9 are the major transporters indicated to cause multidrug resistance in tumor cells by extruding anticancer drugs out of the *** are mainly lipophilic anionic transporters and are reported to transport free or conjugates of glutathione(GSH),glucuronate,or *** addition,MRP1 to MRP3 can transport neutral organic drugs in free form in the presence of free ***,MRPs can transport drugs that differ structurally and mechanistically,including natural anticancer drugs,nucleoside analogs,antimetabolites,and tyrosine kinase *** of these MRPs transport physiologically important anions such as leukotriene C4,bilirubin glucuronide,and cyclic *** review focuses mainly on the physiological functions,cellular resistance characteristics,and probable in vivo role of MRP1 to MRP9.

关键词：多药耐药相关蛋白酪氨酸激酶抑制剂葡萄糖醛酸 MRPs 离子转运抗癌药物肿瘤细胞

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PD173074, a selective FGFR inhibitor, reverses MRP7 (ABCC10)-mediated MDR

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Acta Pharmaceutica Sinica B 2014年第3期4卷 202-207页

作者： Nagaraju Anreddy Atish Patel kamlesh sodani Rishil J.Kathawala Eugenie P.Chen John N.D.Wurpel Zhe-Sheng Chen Department of Pharmaceutical Sciences College of Pharmacy and Health SciencesSt.John's UniversityQueensNY 11439USA

Multidrug resistance protein 7(MRP7,ABCC10)is a recently identified member of the ATP-binding cassette(ABC)transporter family,which adequately confers resistance to a diverse group of antineoplastic agents,including taxanes,vinca alkaloids and nucleoside analogs among *** studies indicate an increased MRP7 expression in non-small cell lung carcinomas(NSCLC)compared to a normal healthy lung *** studies revealed increased paclitaxel sensitivity in the Mrp7^(-/-)mouse model compared to their wild-type *** demonstrates that MRP7 is a key contributor in developing drug *** our group reported that PD173074,a specific fibroblast growth factor receptor(FGFR)inhibitor,could significantly reverse P-glycoprotein-mediated ***,whether PD173074 can interact with and inhibit other MRP members is *** the present study,we investigated the ability of PD173074 to reverse MRP7-mediated *** found that PD173074,at non-toxic concentration,could significantly increase the cellular sensitivity to MRP7 *** studies indicated that PD173074(1μmol/L)significantly increased the intracellular accumulation and in-turn decreased the efflux of paclitaxel by inhibiting the transport activity without altering expression levels of the MRP7 protein,thereby representing a promising therapeutic agent in the clinical treatment of chemoresistant cancer patients.

关键词： PD173074 ABCC10 Fibroblast growth factor receptor Multidrug resistance Tyrosine kinase inhibitor

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Sulindac sulfide selectively increases sensitivity of ABCC1 expressing tumor cells to doxorubicin and glutathione depletion

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The Journal of Biomedical Research 2016年第2期30卷 120-133页

作者： Jason D.Whitt Adam B.Keeton Bernard D.Gary Larry A.Sklar kamlesh sodani Zhe-Sheng Chen Gary A.Piazza Department of Biochemistry University of Mississippi Medical Center Cancer Institute Jackson MS 39216 USA Drug Discovery Research Center Mitchell Cancer Institute University of South Alabama Mobile AL 36604 USA ADT Pharmaceuticals Inc. Orange Beach AL 36561 USA Department of Pathology The University of New Mexico Albuquerque NM87131 USA Department of Pharmaceutical Sciences St. John's University New York NY 11439 USA

ATP-binding cassette（ABC） transporters ABCC1（MRP1）,ABCB1（P-gp）,and ABCG2（BCRP） contribute to chemotherapy *** primary goals of this study were to characterize the efficacy and mechanism of the nonsteroidal anti-inflammatory drug（NSAID）,sulindac sulfide,to reverse ABCC1 mediated resistance to chemotherapeutic drugs and to determine if sulindac sulfide can influence sensitivity to chemotherapeutic drugs independently of drug *** assays were performed to measure resistance of ABC-expressing cell lines to doxorubicin and other chemotherapeutic *** were tested for the ability to restore sensitivity to resistance selected tumor cell lines,as well as a large panel of standard tumor cell *** experiments characterized the mechanism by which sulindac sulfide inhibits ABCC1 substrate and co-substrate（GSH） transport in isolated membrane vesicles and intact *** reversal of multi-drug resistance（MDR）,decreased efflux of doxorubicin,and fluorescent substrates were demonstrated by sulindac sulfide and a related NSAID,indomethacin,in resistance selected and engineered cell lines expressing ABCC 1,but not ABCB 1 or *** sulfide also inhibited transport of leukotriene C_4 into membrane *** sulfide enhanced the sensitivity to doxorubicin in 24 of 47 tumor cell lines,including all melanoma lines tested（7-7）.Sulindac sulfide also decreased intracellular GSH in ABCC1 expressing cells,while the glutathione synthesis inhibitor,BSO,selectively increased sensitivity to sulindac sulfide induced *** sulfide potently and selectively reverses ABCC1-mediated MDR at clinically achievable ***1 expressing tumors may be highly sensitive to the direct cytotoxicity of sulindac sulfide,and in combination with chemotherapeutic drugs that induce oxidative stress.

关键词： multi-drug resistance doxorubicin sulindac MRP1 glutathione

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