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Open AccessArticle

Sitravatinib Sensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Drugs

1
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan
2
Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan
3
Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 10507, Taiwan
4
Department of Chemistry, Tunghai University, Taichung 40704, Taiwan
5
Department of Chinese Medicine, College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan
*
Authors to whom correspondence should be addressed.
Cancers 2020, 12(1), 195; https://doi.org/10.3390/cancers12010195
Received: 22 November 2019 / Revised: 31 December 2019 / Accepted: 8 January 2020 / Published: 13 January 2020
(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)
The development of multidrug resistance (MDR) in cancer patients driven by the overexpression of ATP-binding cassette (ABC) transporter ABCB1 or ABCG2 in cancer cells presents one of the most daunting therapeutic complications for clinical scientists to resolve. Despite many novel therapeutic strategies that have been tested over the years, there is still no approved treatment for multidrug-resistant cancers to date. We have recently adopted a drug repurposing approach to identify therapeutic agents that are clinically active and at the same time, capable of reversing multidrug resistance mediated by ABCB1 and ABCG2. In the present study, we investigated the effect of sitravatinib, a novel multitargeted receptor tyrosine kinase inhibitor, on human ABCB1 and ABCG2 in multidrug-resistant cancer cell lines. We discovered that at submicromolar concentrations, sitravatinib re-sensitizes ABCB1- and ABCG2-overexpressing multidrug-resistant cancer cells to chemotherapeutic drugs. We found that sitravatinib blocks the drug efflux function of ABCB1 and ABCG2 in a concentration-dependent manner but does not significantly alter the protein expression of ABCB1 or ABCG2 in multidrug-resistant cancer cells. In conclusion, we reveal a potential drug repositioning treatment option for multidrug-resistant cancers by targeting ABCB1 and ABCG2 with sitravatinib and should be further investigated in future clinical trials. View Full-Text
Keywords: chemoresistance; MGCD516; modulators; P-glycoprotein; breast cancer resistance protein chemoresistance; MGCD516; modulators; P-glycoprotein; breast cancer resistance protein
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Wu, C.-P.; Hsiao, S.-H.; Huang, Y.-H.; Hung, L.-C.; Yu, Y.-J.; Chang, Y.-T.; Hung, T.-H.; Wu, Y.-S. Sitravatinib Sensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Drugs. Cancers 2020, 12, 195.

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