Abstract
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.
Highlights
The development of multidrug resistance (MDR) in cancer cells, often caused by the overexpression of ATP-binding cassette (ABC) drug transporter, remains a major obstacle in cancer chemotherapy [1,2].These multidrug resistance cancer cells are insensitive to a broad range of chemically unrelated anticancer drugs, which often led to treatment failure, relapse and eventual death of the patients [3,4].Two of the most well-characterized, drug resistance linked ABC drug transporters are ABCB1(MDR1; P-glycoprotein) and ABCG2 (BCRP; MXR) [1,2]
We examined whether cells overexpressing ABCB1 or ABCG2 are less sensitive to sitravatinib than the drug-sensitive counterpart cells
We found that the ABCB1-overexpressing human KB-V-1 epidermal cancer cells (Figure 1a) and the ABCB1-overexpressing human NCI-ADR-RES ovarian cancer cells (Figure 1b) are sensitive to sitravatinib as their drug-sensitive parental KB-3-1 and OVCAR-8 cancer cells, respectively
Summary
The development of multidrug resistance (MDR) in cancer cells, often caused by the overexpression of ATP-binding cassette (ABC) drug transporter, remains a major obstacle in cancer chemotherapy [1,2].These multidrug resistance cancer cells are insensitive to a broad range of chemically unrelated anticancer drugs, which often led to treatment failure, relapse and eventual death of the patients [3,4].Two of the most well-characterized, drug resistance linked ABC drug transporters are ABCB1(MDR1; P-glycoprotein) and ABCG2 (BCRP; MXR) [1,2]. The development of multidrug resistance (MDR) in cancer cells, often caused by the overexpression of ATP-binding cassette (ABC) drug transporter, remains a major obstacle in cancer chemotherapy [1,2]. These multidrug resistance cancer cells are insensitive to a broad range of chemically unrelated anticancer drugs, which often led to treatment failure, relapse and eventual death of the patients [3,4]. Two of the most well-characterized, drug resistance linked ABC drug transporters are ABCB1. Modulating the transport function or the protein expression of ABCB1 and/or ABCG2 is of great clinical significance
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