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Previous studies have shown that small-molecule BCL-2 inhibitors can have a synergistic interaction with ABCG2 substrates in chemotherapy. Venetoclax is a potent and selective BCL-2 inhibitor, approved by the FDA in 2016 for the treatment of patients with chronic lymphocytic leukemia (CLL). This study showed that, at a non-toxic concentration, venetoclax at 10 µM significantly reversed multidrug resistance (MDR) mediated by wild-type ABCG2, without significantly affecting MDR mediated by mutated ABCG2 (R482G and R482T) and ABCB1, while moderate or no reversal effects were observed at lower concentrations (0.5 to 1 µM). The results showed that venetoclax increased the intracellular accumulation of chemotherapeutic agents, which was the result of directly blocking the wild-type ABCG2 efflux function and inhibiting the ATPase activity of ABCG2. Our study demonstrated that venetoclax potentiates the efficacy of wild-type ABCG2 substrate drugs. These findings may provide useful guidance in combination therapy against wild-type ABCG2-mediated MDR cancer in clinical practice.

Overexpression of ATP-binding cassette (ABC) transporters is one of the most important mechanisms responsible for multi-drug resistance (MDR). VS-4718, a tyrosine kinase inhibitor targeting focal adhesion kinase (FAK) with a potential anticancer effect, is currently evaluated in clinical trials. In this study, we investigated whether VS-4718 could reverse MDR mediated by ABC transporters, including ABCB1, ABCG2, and ABCC1. The results showed that VS-4718 significantly reversed ABCB1- and ABCG2-mediated MDR, but not MDR mediated by ABCC1. Treatment of VS-4718 did not alter the protein level and subcellular localization of ABCB1 or ABCG2. Mechanism studies indicated that the reversal effects of VS-4718 were related to attenuation of the efflux activity of ABCB1 and ABCG2 transporters. ATPase analysis indicated that VS-4718 stimulated the ATPase activity of ABCB1 and ABCG2. Docking study showed that VS-4718 interacted with the substrate-binding sites of both ABCB1 and ABCG2, suggesting that VS-4718 may affect the activity of ABCB1 and ABCG2 competitively. This study provided a novel insight for MDR cancer treatment. It indicated that combination of VS-4718 with antineoplastic drugs could attenuate MDR mediated by ABCB1 or ABCG2 in ABCB1- or ABCG2-overexpressing cancer cells.