The effect of levamisole on energy metabolism in Ehrlich ascites tumour cells in vitro.
It has been found that levamisole, an anthelmintic drug, used also as an immunomodulator in human cancer therapy, is a strong inhibitor of tumour aerobic glycolysis. In vitro, in Ehrlich ascites tumour (EAT) cells and supernatants it diminishes glucose uptake and lactate formation. It does not, however, exert a similar inhibitory effect on glycolytic activity in normal liver and muscle supernatants. Metabolic and enzymatic studies have shown that levamisole directly inhibits tumour phosphofructokinase decreasing ATP, as well as 2-phosphoenolpyruvate and pyruvate as further glycolytic intermediates. L-Cysteine used for comparison also as another inhibitor of tumour aerobic glycolysis, decreasing glucose uptake and lactate formation and diminishing pyruvate and ATP levels, differs in the accompanying increase in 2-phosphoenolpyruvate concentration. This crossing-over in metabolite concentration, only seen in tumour material, points to tumour pyruvate kinase as an isoenzyme sensitive to cysteine inhibition. Direct enzymatic studies have confirmed this suggestion. Some similarities in the influence on the metabolism of both compounds studied have been discussed, as well as the role of the effects observed in understanding the mechanisms of levamisole action (also in worms).
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002286:Carcinoma, Ehrlich Tumor / Q000378:metabolism*; D003545:Cysteine / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects*; D006019:Glycolysis / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors; D007773:Lactates / Q000096:biosynthesis; D019344:Lactic Acid; D007978:Levamisole / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D010732:Phosphofructokinase-1 / Q000037:antagonists & inhibitors; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors
D007773:Lactates; D007978:Levamisole; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D010732:Phosphofructokinase-1; D011770:Pyruvate Kinase; D003545:Cysteine