Cellular responses toward cytotoxic drugs are influenced by cross-talk between oncogenic signals and resistance mechanisms. Inhibition of the PI3K/Akt pathway is effective in sensitizing cancer cells of various organs, although the mechanisms have largely remained to be elucidated. Breast cancer resistance protein (BCRP)/ABCG2, a drug efflux pump, confers resistance to multiple anticancer agents such as SN-38 and topotecan. Previous studies reported that inhibition of the PI3K/Akt pathway, by gene knockout or PI3K inhibitors, modulated BCRP-mediated drug transport via BCRP translocation in hematopoietic stem cells, renal polarized cells, and glioma stem-like cells of mammals. In this paper, we tested reversing effects of PI3K inhibitors, LY294002 and wortmannin, on BCRP-mediated anticancer drug resistance of human cancer MCF-7 and A431 cells. LY294002 definitely reversed BCRP-mediated SN-38 and topotecan resistances but wortmannin did not. LY294002 treatment affected neither total nor cell surface BCRP levels by western blotting and flow cytometry but blocked BCRP-mediated topotecan efflux in a dose-dependent manner. Immunohistochemical analyses also demonstrated unchanged cellular BCRP distribution. BCRP overexpression in MCF-7 and A431 cells did not confer LY294002 resistance, suggesting that LY294002 would not be a transported substrate of BCRP. LY294002 is a derivative of quercetin, a member of flavonoid. Taken together, these results suggest that LY294002 inhibits BCRP-mediated drug transport not by BCRP translocation through the PI3K/Akt signal but putatively as a competitive inhibitor in a major subset of cancer cells. Due to its dual effects, LY294002 could be a lead compound for developing more effective and tolerable reagents for cancer treatment.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5612. doi:1538-7445.AM2012-5612