title: Mitochondrial inhibitors show preferential cytotoxicity to human pancreatic cancer PANC-1 cells under glucose-deprived conditions.
abstract: 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.
authors.affiliation: Numazu Bio-Medical Research Institute, Microbial Chemistry Research Center, Shizuoka, Japan. imomose@bikaken.or.jp
authors.forename: Isao
authors.initials: I
authors.lastname: Momose
authors.forename: Shun-Ichi
authors.initials: S
authors.lastname: Ohba
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tatsuda
authors.forename: Manabu
authors.initials: M
authors.lastname: Kawada
authors.forename: Tohru
authors.initials: T
authors.lastname: Masuda
authors.forename: Go
authors.initials: G
authors.lastname: Tsujiuchi
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Esumi
authors.forename: Daishiro
authors.initials: D
authors.lastname: Ikeda
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000172:deficiency*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D010190:Pancreatic Neoplasms / Q000201:enzymology*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C021983:complex V (mitochondrial oxidative phosphorylation system); C077672:efrapeptin F; D025261:Mitochondrial Proton-Translocating ATPases; D005947:Glucose