title: 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.affiliation: Fundación MEDINA. Parque Tecnológico Ciencias de la Salud, Avenida del Conocimiento 3, 18100 Granada, Spain. nuria.de.pedro@medinaandalucia.es
authors.forename: Nuria
authors.initials: N
authors.lastname: de Pedro
authors.forename: Bastien
authors.initials: B
authors.lastname: Cautain
authors.forename: Angeles
authors.initials: A
authors.lastname: Melguizo
authors.forename: Francisca
authors.initials: F
authors.lastname: Vicente
authors.forename: Olga
authors.initials: O
authors.lastname: Genilloud
authors.forename: Fernando
authors.initials: F
authors.lastname: Peláez
authors.forename: Jose R
authors.initials: JR
authors.lastname: Tormo
mesh_terms: D054378:Acetogenins / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000178:diet therapy / Q000201:enzymology* / Q000473:pathology; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D054378:Acetogenins; D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D042967:Electron Transport Complex I