bcrp - publications

Predict more bcrp - ligand interactions now!


1. Oncol Rep. 2012 Mar 15. doi: 10.3892/or.2012.1724. [Epub ahead of print]

The PI3K/Akt inhibitor LY294002 reverses BCRP-mediated drug resistance without
affecting BCRP translocation.

Imai Y, Yoshimori M, Fukuda K, Yamagishi H, Ueda Y.

Department of Pathology, Dokkyo Medical University Koshigaya Hospital, Koshigaya,
Saitama 343-8555, Japan.

Cellular responses toward cytotoxic drugs are influenced by crosstalk between
oncogenic signals and resistance mechanisms. Inhibition of the PI3K/Akt pathway
is effective in sensitizing cancer cells of various organs, although the
mechanisms largely remain 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 study, we
assessed the effects of PI3K inhibitors, LY294002 and wortmannin, on
BCRP-mediated anticancer drug resistance of human cancer MCF-7 and A431 cells.
LY294002, but not wortmannin, reversed the BCRP-mediated SN-38 and topotecan
resistance. LY294002 treatment did not affect total or cell surface BCRP levels
as determined 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 is
not a transported substrate of BCRP. LY294002 is a derivative of quercetin, a
member of flavonoids. 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.

PMID: 22426819 [PubMed - as supplied by publisher]