title: Menadione serves as a substrate for P-glycoprotein: implication in chemosensitizing activity.
abstract: Based on its chemosensitizing effect, we questioned whether menadione is an inhibitor or a substrate of P-glycoprotein (P-gp). To test this hypothesis, we assessed the effect of menadione on P-gp activity and examined the P-gp-dependency of cellular accumulation and cytotoxicity of menadione as well. Treatment with menadione resulted in the concentration-dependent increase of rhodamine 123 (Rh123) accumulation in P-gp-overexpressing MDCKII/MDR1 and NCI/ADR-RES cells, suggesting that menadione inhibits Rh123 extrusion by P-gp. Compared with MDCKII or MCF-7, intracellular distribution of [(3)H]-menadione was significantly lower in MDCKII/MDR1 or NCI/ADR-RES cells, which could be restored by the P-gp inhibitors, verapamil and quinidine. Consistent with these results, MDCKII/MDR1 or NCI/ADR-RES cells were more resistant to the cytotoxicity of menadione than MDCKII or MCF-7 cells, respectively. Such resistance was abolished by the combined treatment of verapamil and quinidine in NCI/ADR-RES cells. Our study identified menadione as a substrate of P-gp, which presumably, acts as the mechanism for the chemosensitizing effect. Menadione may be a promising chemotherapeutic enhancer by its ability of circumventing drug resistance, in addition to its own anti-cancer activity.
authors: College of Pharmacy, Dongguk University, 32 Dongguk-ro, Ilsandong-gu, Goyang, Gyeonggi-do, 410-820, Republic of Korea.
authors: Seok-Jeong
authors: SJ
authors: Oh
authors: Hyo-Kyung
authors: HK
authors: Han
authors: Keon-Wook
authors: KW
authors: Kang
authors: Young-Joo
authors: YJ
authors: Lee
authors: Moo-Yeol
authors: MY
authors: Lee
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D061985:Madin Darby Canine Kidney Cells; D011802:Quinidine / Q000494:pharmacology; D020112:Rhodamine 123 / Q000378:metabolism; D014162:Transfection; D014700:Verapamil / Q000494:pharmacology; D024483:Vitamin K 3 / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D020112:Rhodamine 123; D024483:Vitamin K 3; D014700:Verapamil; D011802:Quinidine