Modulation of doxorubicin cytotoxicity by ethacrynic acid.

Energy-dependent membrane efflux pumps have been implicated in mediating resistance to doxorubicin (DOX). Membrane-transport mechanisms distinct from P-glycoprotein, capable of transporting DOX and glutathione conjugates have been reported in human cells. Since glutathione-conjugate-forming compounds may be candidates for modulating the cytotoxicity of certain anti-neoplastic agents transported by such transport mechanism, the present studies were performed (i) to determine whether ethacrynic acid, a glutathione-conjugate-forming diuretic, can increase DOX cytotoxicity, and (ii) to study the kinetics of DOX transport and its inhibition by the glutathione conjugate of ethacrynic acid (EA-SG) in the H69 human small-cell-lung-cancer cell line and 2 derived DOX-resistant sublines. Our results indicate that more than one DOX transport mechanism may exist in these cell lines, and that glutathione conjugates may be useful for modulating the cytotoxic effects of DOX.