Lactic acid in cancer and mitochondrial disease

Cancer and the mitochondrial diseases are disparate disorders that have in common a failure of normal cellular respiratory activity in disease‐affected tissues. In mitochondrial diseases, the impairment in the mitochondria is often the result of abnormalities in their mtDNA, whereas in cancerous cells, the altered respiration is driven by the Warburg effect. The oxidation of glucose (as pyruvate in the mitochondria) is inhibited and energy production relies on cytoplasmic glycolysis. This suppressed mitochondrial activity confers in tumor cells a state of resistance to apoptosis and, in mitochondrial diseases like mitochondrial encephalopathy, lactic acidosis, and stroke‐like episodes (MELAS), the altered respiration leads to lactic acidosis. Driving glucose to its complete oxidation inside the mitochondria has potential in cancer therapy to reconstitute apoptotic competence in tumor cells and, in mitochondrial disease, to treat lactic acidosis. This minireview investigates the development of small molecule agents for suppressing the Warburg effect in cancer therapy and lactic acidosis in mitochondrial disease. Drug Dev Res 70:499–511, 2009.