Abstract
Overexpression of ABCG2 remains a major impediment to successful cancer treatment, because ABCG2 functions as an efflux pump of chemotherapeutic agents and causes clinical multidrug resistance (MDR). Therefore, it is important to uncover effective modulators to circumvent ABCG2-mediated MDR in cancers. In this study, we reported that AZ-628, a RAF kinase inhibitor, effectively antagonizes ABCG2-mediated MDR in vitro. Our results showed that AZ-628 completely reversed ABCG2-mediated MDR at a non-toxic concentration (3 μM) without affecting ABCB1-, ABCC1-, or ABCC10 mediated MDR. Further studies revealed that the reversal mechanism was by attenuating ABCG2-mediated efflux and increasing intracellular accumulation of ABCG2 substrate drugs. Moreover, AZ-628 stimulated ABCG2-associated ATPase activity in a concentration-dependent manner. Docking and molecular dynamics simulation analysis showed that AZ-628 binds to the same site as ABCG2 substrate drugs with higher score. Taken together, our studies indicate that AZ-628 could be used in combination chemotherapy against ABCG2-mediated MDR in cancers.
Highlights
Multidrug resistance (MDR) is a major barrier of successful chemotherapy (Gottesman and Ambudkar, 2001)
AZ-628 showed exquisite efficacy in cell lines harboring the V600E BRAF mutations compared with sorafenib, a FDA-approved RAF kinase inhibitor for renal and hepatocellular carcinoma (McDermott et al, 2007)
We reported that AZ-628 significantly sensitized ABCG2-mediated multidrug resistance (MDR) to ABCG2 substrate drugs at a non-toxic concentration in cancer cells
Summary
Multidrug resistance (MDR) is a major barrier of successful chemotherapy (Gottesman and Ambudkar, 2001). Up-regulation of ATP-binding cassette (ABC) transporters, energized by ATP hydrolysis to mediate active transportation of substrate drugs, is the major one in MDR cancer cells (Borst and Elferink, 2002; Teodori et al, 2006; Cui et al, 2018). ABCG2 expresses ubiquitously in organs and tissues including small intestine, liver, colon, and placenta, where ABCG2 plays the role of protecting normal cells from accumulation of toxins (Honjo et al, 2001; Zaher et al, 2006; Mao and Unadkat, 2015). ABCG2 has been detected in various cancer cells including breast, lung, bladder, and colon cancers (Mao and Unadkat, 2015). Common substrates of ABCG2 include mitoxantrone, SN-38, and topotecan (Zaher et al, 2006)
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