Masitinib antagonizes ATP-binding cassette subfamily G member 2-mediated multidrug resistance

Kathawala,Rishil J.; Chen,Jun-Jiang; Zhang,Yun-Kai; Wang,Yi-Jun; Patel,Atish; Wang,De-Shen; Talele,Tanaji T.; Ashby,Charles R.; Chen,Zhe-Sheng

doi:10.3892/ijo.2014.2341

Masitinib antagonizes ATP-binding cassette subfamily G member 2-mediated multidrug resistance

Authors:
- Rishil J. Kathawala
- Jun-Jiang Chen
- Yun-Kai Zhang
- Yi-Jun Wang
- Atish Patel
- De-Shen Wang
- Tanaji T. Talele
- Charles R. Ashby
- Zhe-Sheng Chen
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Affiliations: Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA
Published online on: March 13, 2014 https://doi.org/10.3892/ijo.2014.2341
Pages: 1634-1642

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Abstract

In this in vitro study, we determined whether masitinib could reverse multidrug resistance (MDR) in cells overexpressing the ATP binding cassette subfamily G member 2 (ABCG2) transporter. Masitinib (1.25 and 2.5 µM) significantly decreases the resistance to mitoxantrone (MX), SN38 and doxorubicin in HEK293 and H460 cells overexpressing the ABCG2 transporter. In addition, masitinib (2.5 µM) significantly increased the intracellular accumulation of [3H]-MX, a substrate for ABCG2, by inhibiting the function of ABCG2 and significantly decreased the efflux of [3H]-MX. However, masitinib (2.5 µM) did not significantly alter the expression of the ABCG2 protein. In addition, a docking model suggested that masitinib binds within the transmembrane region of a homology-modeled human ABCG2 transporter. Overall, our in vitro findings suggest that masitinib reverses MDR to various anti-neoplastic drugs in HEK293 and H460 cells overexpressing ABCG2 by inhibiting their transport activity as opposed to altering their levels of expression.

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