title: Masitinib antagonizes ATP-binding cassette subfamily C member 10-mediated paclitaxel resistance: a preclinical study.
abstract: Paclitaxel displays clinical activity against a wide variety of solid tumors. However, resistance to paclitaxel significantly attenuates the response to chemotherapy. The ABC transporter subfamily C member 10 (ABCC10), also known as multidrug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance. In this study, we show that masitinib, a small molecule stem-cell growth factor receptor (c-Kit) tyrosine kinase inhibitor, at nontoxic concentrations, significantly attenuates paclitaxel resistance in HEK293 cells transfected with ABCC10. Our in vitro studies indicated that masitinib (2.5 μmol/L) enhanced the intracellular accumulation and decreased the efflux of paclitaxel by inhibiting the ABCC10 transport activity without altering the expression level of ABCC10 protein. Furthermore, masitinib, in combination with paclitaxel, significantly inhibited the growth of ABCC10-expressing tumors in nude athymic mice in vivo. Masitinib administration also resulted in a significant increase in the levels of paclitaxel in the plasma, tumors, and lungs compared with paclitaxel alone. In conclusion, the combination of paclitaxel and masitinib could serve as a novel and useful therapeutic strategy to reverse paclitaxel resistance mediated by ABCC10.
authors.affiliation: Corresponding Authors: Zhe-Sheng Chen, Department of Pharmaceutical Sciences, St. John's University, Queens, NY 11439. chenz@stjohns.edu.
authors.forename: Rishil J
authors.initials: RJ
authors.lastname: Kathawala
authors.forename: Kamlesh
authors.initials: K
authors.lastname: Sodani
authors.forename: Kang
authors.initials: K
authors.lastname: Chen
authors.forename: Atish
authors.initials: A
authors.lastname: Patel
authors.forename: Alaa H
authors.initials: AH
authors.lastname: Abuznait
authors.forename: Nagaraju
authors.initials: N
authors.lastname: Anreddy
authors.forename: Yue-Li
authors.initials: YL
authors.lastname: Sun
authors.forename: Amal
authors.initials: A
authors.lastname: Kaddoumi
authors.forename: Charles R
authors.initials: CR
authors.lastname: Ashby
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001549:Benzamides; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage*; D010880:Piperidines; D011725:Pyridines; D013844:Thiazoles / Q000008:administration & dosage*
chemical_list: D001549:Benzamides; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; D010880:Piperidines; D011725:Pyridines; D013844:Thiazoles; C421142:ABCC10 protein, human; C526575:masitinib