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: Isao Momose, Shun-Ichi Ohba, Daisuke Tatsuda, Manabu Kawada, Tohru Masuda, Go Tsujiuchi, Takao Yamori, Hiroyasu Esumi, Daishiro Ikeda
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 392 Issue 3 Pg. 460-6 (Feb 12 2010) ISSN: 1090-2104 [Electronic] United States
• PMID: 20083087 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Intercellular Signaling Peptides and Proteins
• Peptides
• complex V (mitochondrial oxidative phosphorylation system)
• efrapeptin F
• Mitochondrial Proton-Translocating ATPases
• Glucose

Topics

• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Enzyme Inhibitors (pharmacology)
• Glucose (deficiency)
• Humans
• Intercellular Signaling Peptides and Proteins
• Mitochondrial Proton-Translocating ATPases (antagonists & inhibitors)
• Pancreatic Neoplasms (enzymology)
• Peptides (chemistry, pharmacology)