WHI‐P154 enhances the chemotherapeutic effect of anticancer agents in ABCG2‐overexpressing cells

Cancer Science

Hui Zhang³  Yun-Kai Zhang²  Yi-Jun Wang²  Rishil J. Kathawala²  Atish Patel²  Hua Zhu¹  Kamlesh Sodani²  Tanaji T. Talele²  Suresh V. Ambudkar⁴  Zhe-Sheng Chen² 

[1] Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA;Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St John's University, Queens, New York, USA;Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China;Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA

关键词: ABCG2 protein;    ATP‐binding cassette transporters;    multidrug resistance;    tyrosine kinase;    WHI‐P154;   

DOI  :  10.1111/cas.12462

来源: Wiley

【 摘 要 】

Abstract

ATP-binding cassette (ABC) transmembrane proteins evidently decrease the intracellular accumulation of substrate chemotherapeutic drugs by extruding them against a concentration gradient, thereby inducing drug resistance. Here we reported the effect of WHI-P154, an irreversible inhibitor of Janus kinase 3 and epidermal growth factor receptor tyrosine kinases, on reversing ABC transporters-mediated drug resistance. We found that WHI-P154 significantly enhanced the sensitivity of ABCG2-overexpressing cells to its substrates. WHI-P154 moderately sensitized ABCB1-overexpressing KB-C2 cells to its substrates whereas showed no sensitizing effect on ABCC1-, ABCC2 or ABCC10-mediated drug resistance. Moreover, WHI-P154 produced a significant increase in the intracellular accumulation of [³H]-mitoxantrone in ABCG2-overexpressing cells. The expression levels nor the localization of the ABCG2 protein was altered after treatment of ABCG2-overexpressing cells with WHI-P154. Further studies indicated that WHI-P154 enhanced the ATPase activity of ABCG2 at low concentrations (<10 μM). Additionally, a docking model predicted the binding conformation of WHI-P154 within the transmembrane region of homology-modeled human ABCG2 transporter. Collectively, these findings highlighted WHI-P154 could significantly reverse ABCG2-mediated multidrug drug resistance by directly blocking the efflux function.

【 授权许可】

CC BY-NC-ND   
© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

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