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IvermectinによるP-糖蛋白質関与の多剤耐性克服作用：古沢　忍，高柳義男，佐々木健一（東北薬大・癌研）

Circumvention of P-glycoprotein mediated multidrug resistance by ivermectin : Shinobu FURUSAWA, Yoshio TAKAYANAGI, Ken-ichi SASAKI (Dept. Pharmacol. & Toxicol., Cancer Res. Inst., Tohoku College of Pharmacy)

Overexpression of P-glycoprotein (P-gp) by tumors results in multidrug resistance (MDR) to structurally unrelated oncolytic. Acquired MDR is a major factor in the failure of doxorubicin (DOX) -based cancer chemotherapy. The present study evaluates ivermectin as a modulator in a DOX-resistant leukemia cell lines (mouse P388/DOX and human K562/DOX). Sensitive and resistant cells expressing P-gp were identified by monoclonal antibodies C219 and MRK-16. In vitro cytotoxicity studies using the microculture tetrazolium assay have shown that ivermectin reverses resistance to DOX in the P388/DOX and K562/DOX cell lines at a concentration of 100-2000 nM. A significant increase in apoptotic cells by ivermectin was observed in resistant cells treated with DOX. Ivermectin dramatically increased the accumulations of DOX and rhodamine 123 by the resistant cells, while the compound had no affect on DOX accumulation in the parent cells. Continuous exposure of resistant cells to DOX and ivermectin results in the expression of Fas antigen and production of reactive oxygen species in cells. These results of our study show that ivermectin interacts with P-gp and is a potent MDR reversing agent.