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

Authors

  • Hui Zhang,

    1. Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
    2. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St John's University, Queens, New York, USA
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  • Yun-Kai Zhang,

    1. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St John's University, Queens, New York, USA
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  • Yi-Jun Wang,

    1. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St John's University, Queens, New York, USA
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  • Rishil J. Kathawala,

    1. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St John's University, Queens, New York, USA
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  • Atish Patel,

    1. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St John's University, Queens, New York, USA
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  • Hua Zhu,

    1. Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
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  • Kamlesh Sodani,

    1. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St John's University, Queens, New York, USA
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  • Tanaji T. Talele,

    1. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St John's University, Queens, New York, USA
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  • Suresh V. Ambudkar,

    1. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
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  • Zhe-Sheng Chen,

    Corresponding author
    1. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St John's University, Queens, New York, USA
    • Correspondence

      Li-Wu Fu, State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, China.

      Tel: +86-20-873-431-63; Fax: +86-20-873-431-70;

      E-mail: fulw@mail.sysu.edu.cn

      and

      Zhe-Sheng Chen, Department of Pharmaceutical Sciences, St. John's University, Queens, New York 11439, USA.

      Tel: +1-718-990-1432; Fax: +1-718-990-1877;

      E-mail: chenz@stjohns.edu

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  • Li-Wu Fu

    Corresponding author
    1. Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
    • Correspondence

      Li-Wu Fu, State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, China.

      Tel: +86-20-873-431-63; Fax: +86-20-873-431-70;

      E-mail: fulw@mail.sysu.edu.cn

      and

      Zhe-Sheng Chen, Department of Pharmaceutical Sciences, St. John's University, Queens, New York 11439, USA.

      Tel: +1-718-990-1432; Fax: +1-718-990-1877;

      E-mail: chenz@stjohns.edu

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  • Funding information

    This work was supported by St. John's University Research Seed grant (No. 579-1110-7002) to Z.S. Chen, the Major science and technology project of the National National Natural Sciences Foundation of China grant (No. 81072669 and No. 81061160507) for L.W. Fu, and Sun Yat-Sen University Ph. D. visiting scholar abroad program and international collaborative research project of Guangdong Province. Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research

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.

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