title: Relevance of the OCT1 transporter to the antineoplastic effect of biguanides.
abstract: Epidemiologic and laboratory data suggesting that metformin has antineoplastic activity have led to ongoing clinical trials. However, pharmacokinetic issues that may influence metformin activity have not been studied in detail. The organic cation transporter 1 (OCT1) is known to play an important role in cellular uptake of metformin in the liver. We show that siRNA knockdown of OCT1 reduced sensitivity of epithelial ovarian cancer cells to metformin, but interestingly not to another biguanide, phenformin, with respect to both activation of AMP kinase and inhibition of proliferation. We observed that there is heterogeneity between primary human tumors with respect to OCT1 expression. These results suggest that there may be settings where drug uptake limits direct action of metformin on neoplastic cells, raising the possibility that metformin may not be the optimal biguanide for clinical investigation.
authors: Division of Gynecologic Oncology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors: Eric D
authors: ED
authors: Segal
authors: Amber
authors: A
authors: Yasmeen
authors: Marie-Claude
authors: MC
authors: Beauchamp
authors: Joshua
authors: J
authors: Rosenblatt
authors: Michael
authors: M
authors: Pollak
authors: Walter H
authors: WH
authors: Gotlieb
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001645:Biguanides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D008687:Metformin / Q000494:pharmacology; D027702:Organic Cation Transporter 1 / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010629:Phenformin / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001645:Biguanides; D027702:Organic Cation Transporter 1; D034741:RNA, Small Interfering; D008687:Metformin; D010629:Phenformin; D000263:Adenylate Kinase