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.
Momose
Isao
I
Numazu Bio-Medical Research Institute, Microbial Chemistry Research Center, Shizuoka, Japan. imomose@bikaken.or.jp
Ohba
Shun-Ichi
S
Tatsuda
Daisuke
D
Kawada
Manabu
M
Masuda
Tohru
T
Tsujiuchi
Go
G
Yamori
Takao
T
Esumi
Hiroyasu
H
Ikeda
Daishiro
D
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*
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