Characterization of a Potent, Selective, and Safe Inhibitor, Ac15(Az8)₂, in Reversing Multidrug Resistance Mediated by Breast Cancer Resistance Protein (BCRP/ABCG2).

ABSTRACT: Overexpression of breast cancer resistance transporter (BCRP/ABCG2) in cancers has been explained for the failure of chemotherapy in clinic. Inhibition of the transport activity of BCRP during chemotherapy should reverse multidrug resistance. In this study, a triazole-bridged flavonoid dimer Ac15(Az8)₂ was identified as a potent, nontoxic, and selective BCRP inhibitor. Using BCRP-overexpressing cell lines, its EC₅₀ for reversing BCRP-mediated topotecan resistance was 3 nM in MCF7/MX100 and 72 nM in S1M180 in vitro. Mechanistic studies revealed that Ac15(Az8)₂ restored intracellular drug accumulation by inhibiting BCRP-ATPase activity and drug efflux. It did not down-regulate the cell surface BCRP level to enhance drug retention. It was not a t

SUBMITTER: Chong TC 

PROVIDER: S-EPMC9653733 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature