Menadione serves as a substrate for P-glycoprotein: implication in chemosensitizing activity

다국어 초록 (Multilingual Abstract)

Based on its chemosensitizing effect, we questionedwhether menadione is an inhibitor or a substrate ofP-glycoprotein (P-gp). To test this hypothesis, we assessedthe effect of menadione on P-gp activity and examined theP-gp-dependency of cellular accumulation and cytotoxicityof menadione as well. Treatment with menadione resultedin the concentration-dependent increase of rhodamine 123(Rh123) accumulation in P-gp-overexpressing MDCKII/MDR1 and NCI/ADR-RES cells, suggesting that menadioneinhibits Rh123 extrusion by P-gp. Compared withMDCKII or MCF-7, intracellular distribution of [3H]-menadione was significantly lower in MDCKII/MDR1 orNCI/ADR-RES cells, which could be restored by the P-gpinhibitors, verapamil and quinidine. Consistent with theseresults, MDCKII/MDR1 or NCI/ADR-RES cells weremore resistant to the cytotoxicity of menadione thanMDCKII or MCF-7 cells, respectively. Such resistance wasabolished by the combined treatment of verapamil andquinidine in NCI/ADR-RES cells. Our study identifiedmenadione as a substrate of P-gp, which presumably, actsas the mechanism for the chemosensitizing effect. Menadionemay be a promising chemotherapeutic enhancer byits ability of circumventing drug resistance, in addition toits own anti-cancer activity.

참고문헌 (Reference)

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