Inhibition of glycolysis of mammalian cells by misonidazole and other radiosensitizing drugs: Prevention by thiols

Prolonged anaerobic incubation of Ehrlich ascites tumor cells and Chinese hamster V79–379A cells with misonidazole, desmethylmisonidazole, or niridazole led to inhibition of both glucose consumption and lactate formation. This effect was measured in cells washed free of the nitro compounds and resuspended in fresh buffer or medium. The degree of inhibition of glucose utilization was related to drug concentration, and to the rate of metabolic reduction, as measured under aerobic conditions by KCN-insensitive oxygen consumption. Misonidazole-induced inhibition of glycolysis developed concurrently with depletion of intracellular non-protein thiol (NPSH) and was protected against by the presence of cysteamine, cysteine and, to some extent, GSH in the cell incubate. These findings suggest reaction of reduced drug intermediates with thiol-containing enzymes. The glutathione-reactive agent diethyl maleate was used to deplete 90% of the endogenous NPSH, but this depletion did not alter the effects of misonidazole on glycolysis.