Fundación MEDINA. Parque Tecnológico Ciencias de la Salud, Avenida del Conocimiento 3, 18100 Granada, Spain.
J Bioenerg Biomembr. 2013 Feb;45(1-2):153-64. doi: 10.1007/s10863-012-9489-1. Epub 2012 Nov 21.
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.
新型抗肿瘤药物的开发是癌症化疗的关键问题，因为很可能某些癌细胞对当前的化疗具有耐药性。在过去的二十年中，我们对癌症发病机制的理解取得了巨大的进展。这些进展使我们能够鉴定出新的靶标，如癌基因、肿瘤抑制基因和线粒体的可能作用（Fulda 等人，Nat Rev Drug Discov 9:447-464, 2010）。由于 Annonaceous Acetogenins（ACGs）与线粒体复合物 I 相互作用，因此被描述为呼吸链最有效的抑制剂（Degli Esposti 和 Ghelli，Biochim Biophys Acta 1187:116-120, 1994；Zafra-Polo 等人，Phytochemistry 42:253-271, 1996；Miyoshi 等人，Biochim Biophys Acta 1365:443-452, 1998；Tormo 等人，Arch Biochem Biophys 369:119-126, 1999；Motoyama 等人，Bioorg Med Chem Lett 12:2089-2092, 2002）。为了探索 Annonaceous 植物天然产物在癌症治疗中的可能应用，我们选择了四种双四氢呋喃 ACGs，三种来自 Annona cherimolia（cherimolin-1、motrilin 和 laherradurin），一种来自 Rollinia mucosa（rollinianstatin-1），以充分描述它们在细胞内的作用机制（图 1）。在这项研究中，我们使用肝癌细胞系（HepG2）作为模型，表明双四氢呋喃 ACGs 通过诱导细胞凋亡线粒体途径导致细胞死亡。我们比较了它们的效力和行为与经典的线粒体呼吸链复合物 I 抑制剂鱼藤酮在每个凋亡途径步骤中的表现。
