vitamin-k-semiquinone-radical and ellipticine

The cytotoxicities of mitomycin C (MMC) and doxorubicin (DOX) have been proposed to depend on intracellular reduction by reduced flavoproteins. We investigated whether MMC- and DOX-induced cytotoxicity could be inhibited by competing for electrons from reduced flavoproteins by the artificial electron acceptors phenazine methosulfate (PMS), menadione (MEN) and methylene blue (MB). In intact SW-1573 human lung tumor cells these compounds proved to be excellent electron acceptors, as judged from their capacity to induce high levels of cyanide-resistant respiration. In addition, PMS, MEN and MB were found to decrease the cytotoxicity of MMC, by 90, 63 and 29%, respectively, at concentrations that were themselves completely nontoxic. In contrast, DOX cytotoxicity was not detectably affected. These results suggest that in SW-1573 cells flavoprotein-mediated bioreduction is required for the cytotoxic effect of MMC, but not for that of DOX.

Topics: Carcinoma, Squamous Cell; Doxorubicin; Drug Interactions; Ellipticines; Humans; Lung Neoplasms; Methylene Blue; Methylphenazonium Methosulfate; Mitomycin; Mitomycins; Oxygen Consumption; Peroxides; Phenazines; tert-Butylhydroperoxide; Tumor Cells, Cultured; Vitamin K