Effect of artificial electron acceptors on the cytotoxicity of mitomycin C and doxorubicin in human lung tumor cells.
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.
Keizer
H G
HG
Department of Radiotherapy, Free University, Amsterdam, The Netherlands.
De Leeuw
S J
SJ
Van Rijn
J
J
Pinedo
H M
HM
Joenje
H
H
D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism; D004317:Doxorubicin / Q000627:therapeutic use*; D004347:Drug Interactions; D004611:Ellipticines / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008751:Methylene Blue / Q000494:pharmacology*; D008773:Methylphenazonium Methosulfate / Q000494:pharmacology*; D016685:Mitomycin; D008937:Mitomycins / Q000627:therapeutic use*; D010101:Oxygen Consumption / Q000187:drug effects; D010545:Peroxides / Q000494:pharmacology; D010619:Phenazines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014812:Vitamin K / Q000494:pharmacology*; D020122:tert-Butylhydroperoxide
D004611:Ellipticines; D008937:Mitomycins; D010545:Peroxides; D010619:Phenazines; C034192:ellipticine; D014812:Vitamin K; D008773:Methylphenazonium Methosulfate; D016685:Mitomycin; D004317:Doxorubicin; D020122:tert-Butylhydroperoxide; D008751:Methylene Blue