MY-5445, a phosphodiesterase type 5 inhibitor, resensitizes ABCG2-overexpressing multidrug-resistant cancer cells to cytotoxic anticancer drugs.

ABSTRACT: The overexpression of one or multiple ATP-binding cassette (ABC) transporters such as ABCB1, ABCC1 or ABCG2 in cancer cells often leads to the development of multidrug resistance phenotype and consequent treatment failure. Therefore, these transporters constitute an important target to improve the therapeutic outcome in cancer patients. In this study, we employed a drug repurposing approach to identify MY-5445, a known phosphodiesterase type 5 inhibitor, as a selective modulator of ABCG2. We discovered that by inhibiting the drug transport function of ABCG2, MY-5445 potentiates drug-induced apoptosis in ABCG2-overexpressing multidrug-resistant cancer cells and resensitizes these cells to chemotherapeutic drugs. Our data of MY-5445 stimulating the ATPase activity of ABCG2 and molecular docking analysis of its binding to the substrate-binding pocket of ABCG2 provide additional insight into the manner in which MY-5445 interacts with ABCG2. Furthermore, we found that ABCG2 does not confer resistance to MY-5445 in human cancer cells. Overall, our study revealed an additional action of MY-5445 to resensitize ABCG2-overexpressing multidrug-resistant cancer cells to conventional anticancer drugs, and this should be evaluated in future drug combination trials.

SUBMITTER: Wu CP 

PROVIDER: S-EPMC7017726 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature