@article{e7151cd9b8e345f19e4780483fa806a4,
title = "BMS-599626, a highly selective pan-her kinase inhibitor, antagonizes ABCG2-mediated drug resistance",
abstract = "Multidrug resistance (MDR) associated with the overexpression of ABC transporters is one of the key causes of chemotherapy failure. Various compounds blocking the function and/or downregulating the expression of these transporters have been developed over the last few decades. However, their potency and toxicity have always been a concern. In this report, we found that BMS-599626 is a highly potent inhibitor of the ABCG2 transporter, inhibiting its efflux function at 300 nM. Our study repositioned BMS-599626, a highly selective pan-HER kinase inhibitor, as a chemosensitizer in ABCG2-overexpressing cell lines. As shown by the cytotoxicity assay results, BMS-599626, at noncytotoxic concentrations, sensitizes ABCG2-overexpressing cells to topotecan and mitoxantrone, two well-known substrates of ABCG2. The results of our radioactive drug accumulation experiment show that the ABCG2-overexpressing cells, treated with BMS-599626, had an increase in the accumulation of substrate chemotherapeutic drugs, as compared to their parental subline cells. Moreover, BMS-599626 did not change the protein expression or cell surface localization of ABCG2 and inhibited its ATPase activity. Our in-silico docking study also supports the interaction of BMS-599626 with the substrate-binding site of ABCG2. Taken together, these results suggest that administration of chemotherapeutic drugs, along with nanomolar concentrations (300 nM) of BMS-599626, may be effective against ABCG2-mediated MDR in clinical settings.",
keywords = "ABC transporters, ABCG2, BMS-599626, Chemotherapy, HER kinase inhibitor, Multidrug resistance",
author = "Ashar, {Yunali V.} and Jingchun Zhou and Pranav Gupta and Teng, {Qiu Xu} and Lei, {Zi Ning} and Reznik, {Sandra E.} and Sabrina Lusvarghi and John Wurpel and Ambudkar, {Suresh V.} and Chen, {Zhe Sheng}",
note = "Funding Information: This work was partially supported by Department of Pharmaceutical Sciences, St. John{\textquoteright}s University. S.L and S.V.A were supported by The Intramural Research Program of the National Institute of Health, National Cancer Institute, Center for Cancer Research. Acknowledgments: The authors are thankful to Susan E. Bates (Columbia University, NY, USA) and Robert W. Robey (NIH, MD, USA) for providing SW620, SW620/AD300, NCI-H460/MX20, and ABCG2-transfected cell lines. We would like to extend our gratitude to Shin-Ichi Akiyama for providing KB-3-1 and KB-CV60 cell lines and to Mark F. Rosenberg (University of Manchester, Manchester, UK) and Zsolt Bik{\'a}di (Virtua Drug Ltd., Budapest, Hungary) for providing coordinates for the ABCG2 homology model. Our sincere thanks to Tanaji T. Talele (St. John{\textquoteright}s University, New York, NY, USA) for providing the computing resources for docking analysis. We thank Chemie-Tek (Indianapolis, IN, USA) for providing us with a free sample of BMS-599626. Funding Information: Funding: This work was partially supported by Department of Pharmaceutical Sciences, St. John{\textquoteright}s University. S.L and S.V.A were supported by The Intramural Research Program of the National Institute of Health, National Cancer Institute, Center for Cancer Research. Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2020",
month = sep,
doi = "10.3390/cancers12092502",
language = "English (US)",
volume = "12",
pages = "1--15",
journal = "Cancers",
issn = "2072-6694",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "9",
}