title: The PI3K/Akt inhibitor LY294002 reverses BCRP-mediated drug resistance             without affecting BCRP translocation.
abstract: 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.
authors.affiliation: Department of Pathology, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Saitama 343-8555, Japan. ya-imai@dokkyomed.ac.jp
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Imai
authors.forename: Mayumi
authors.initials: M
authors.lastname: Yoshimori
authors.forename: Kazunori
authors.initials: K
authors.lastname: Fukuda
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Yamagishi
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Ueda
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000730:Androstadienes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D000077146:Irinotecan; D009025:Morpholines / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019772:Topotecan / Q000494:pharmacology*; D000077191:Wortmannin
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000730:Androstadienes; D000970:Antineoplastic Agents; D002166:Camptothecin; D002867:Chromones; D004791:Enzyme Inhibitors; D000077146:Irinotecan; D009025:Morpholines; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019772:Topotecan; D000077191:Wortmannin; C116614:ABCG2 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one