Mitochondrial complex I inhibitors, acetogenins, induce HepG2 cell death through the induction of the complete apoptotic mitochondrial pathway.

Abstract

The development of new anti-neoplastic drugs is a key issue for cancer chemotherapy due to the reality that, most likely, certain cancer cells are resistant to current chemotherapy. The past two decades have witnessed tremendous advances in our understanding of the pathogenesis of cancer. These advances have allowed identification new targets as oncogenes, tumor supressor genes and the possible implication of the mitochondria (Fulda et al. Nat Rev Drug Discov 9:447-464, 2010). Annonaceous Acetogenins (ACGs) have been described as the most potent inhibitors of the respiratory chain because of their interaction with mitochondrial Complex I (Degli Esposti and Ghelli Biochim Biophys Acta 1187:116-120, 1994; Zafra-Polo et al. Phytochemistry 42:253-271, 1996; Miyoshi et al. Biochim Biophys Acta 1365:443-452, 1998; Tormo et al. Arch Biochem Biophys 369:119-126, 1999; Motoyama et al. Bioorg Med Chem Lett 12:2089-2092, 2002). To explore a possible application of natural products from Annonaceous plants to cancer treatment, we have selected four bis-tetrahydrofuranic ACGs, three from Annona cherimolia (cherimolin-1, motrilin and laherradurin) and one from Rollinia mucosa (rollinianstatin-1) in order to fully describe their mechanisms responsible within the cell (Fig. 1). In this study, using a hepato-carcinoma cell line (HepG2) as a model, we showed that the bis-THF ACGs caused cell death through the induction of the apoptotic mitochondrial pathway. Their potency and behavior were compared with the classical mitochondrial respiratory chain Complex I inhibitor rotenone in every apoptotic pathway step.

• Authors: Nuria de Pedro, Bastien Cautain, Angeles Melguizo, Francisca Vicente, Olga Genilloud, Fernando Peláez, Jose R Tormo
• Journal: Journal of bioenergetics and biomembranes (J Bioenerg Biomembr) Vol. 45 Issue 1-2 Pg. 153-64 (Feb 2013) ISSN: 1573-6881 [Electronic] United States
• PMID: 23180140 (Publication Type: Journal Article)

Chemical References

• Acetogenins
• Enzyme Inhibitors
• Mitochondrial Proteins
• Neoplasm Proteins
• Electron Transport Complex I

Topics

• Acetogenins (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Hepatocellular (drug therapy, enzymology, pathology)
• Electron Transport Complex I (antagonists & inhibitors, metabolism)
• Enzyme Inhibitors (pharmacology)
• Hep G2 Cells
• Humans
• Liver Neoplasms (diet therapy, enzymology, pathology)
• Mitochondria (enzymology, pathology)
• Mitochondrial Proteins (antagonists & inhibitors, metabolism)
• Neoplasm Proteins (antagonists & inhibitors, metabolism)