Modulating the function of ABCB1: in vitro and in vivo characterization of sitravatinib, a tyrosine kinase inhibitor

作     者：Yuqi Yang Ning Ji Chao-Yun Cai Jing-Quan Wang Zi-Ning Lei Qiu-Xu Teng Zhuo-Xun Wu Qingbin Cui Yihang Pan Zhe-Sheng Chen 

作者机构：Department of Pharmaceutical SciencesCollege of Pharmacy and Health SciencesSt.John’s UniversityQueensNew York 11439USA State Key Laboratory of Experimental HematologyChinese Academy of Medical Science and Peking Union Medical CollegeInstitute of Hematology and Blood Diseases HospitalTianjin 300020P.R.China School of Public HealthGuangzhou Medical UniversityGuangzhouGuangdong 511436P.R.China Tomas Lindahl Nobel Laureate Laboratorythe Seventh Affiliated Hospital of Sun Yat-sen UniversityShenzhenGuangdong 518107P.R.China 

出 版 物：《Cancer Communications》 (癌症通讯（英文）)

年 卷 期：2020年第40卷第7期

页      面：285-300页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by NIH(No.1R15GM116043-01) National Natural Science Foundation of China(No.81872901)as well as some supports from Department of Pharmaceutical Sciences,St.John’s University 

主　　题：Sitravatinib 

摘      要：Background:Overexpression of ATP-binding cassette(ABC)transporter is a major contributor to multidrug resistance(MDR),in which cancer cells acquire resistance to a wide spectrum of chemotherapeutic *** this work,we evaluated the sensitizing effect of sitravatinib,a broad-spectrum tyrosine kinase inhibitor(TKI),on ATP-binding cassette subfamily B member 1(ABCB1)-and ATP-binding cassette subfamily C member 10(ABCC10)-mediated ***:MTT assay was conducted to examine cytotoxicity and evaluate the sensitizing effect of sitravatinib at non-toxic ***-labeled paclitaxel transportation,Western blotting,immunofluorescence analysis,and ATPase assay were carried out to elucidate the mechanism of sitravatinib-induced *** in vitro findings were translated into preclinical evaluation with the establishment of xenograft ***:Sitravatinib considerably reversed MDR mediated by ABCB1 and partially antagonized ABCC10-mediated *** in silico docking simulation analysis indicated that sitravatinib strongly and stably bound to the transmembrane domain of ABCB1 human-mouse chimeric ***,sitravatinib inhibited hydrolysis of ATP and synchronously decreased the efflux function of ***,sitravatinib could considerably enhance the intracellular concentration of anticancer ***,no significant alterations of both expression level and localization of ABCB1 were *** importantly,sitravatinib could remarkably restore the antitumor activity of vincristine in ABCB1-mediated xenograft model without observable toxic ***:The findings in this study suggest that the combination of sitrvatinib and substrate antineoplastic drugs of ABCB1 could attenuate the MDR mediated by the overexpression of ABCB1.