Mitochondrial inhibitors show preferential cytotoxicity to human pancreatic cancer PANC-1 cells under glucose-deprived conditions

Large areas of tumor are nutrient-starved and hypoxic due to a disorganized vascular system. Therefore, we screened small molecules to identify cytotoxic agents that function preferentially in nutrient-starved conditions. We found that efrapeptin F had preferential cytotoxicity to nutrient-deprived cells compared with nutrient-sufficient cells. Because efrapeptin F acts as a mitochondrial complex V inhibitor, we examined whether inhibitors of complex I, II, III, and V function as cytotoxic agents preferentially in nutrient-deprived cells. Interestingly, these inhibitors showed preferential cytotoxicity to nutrient-deprived cells and caused cell death under glucose-limiting conditions, irrespective of the presence or absence of amino acids and/or serum. In addition, these inhibitors were preferentially cytotoxic to nutrient-deprived cells even under hypoxic conditions. Further, efrapeptin F showed antitumor activity in vivo. These data indicate that mitochondrial inhibitors show preferential cytotoxicity to cancer cells under glucose-limiting conditions, and these inhibitors offer a promising strategy for anticancer therapeutic.