CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
Bioorg Med Chem. 2013 Dec 1;21(23):7239-49. doi: 10.1016/j.bmc.2013.09.066. Epub 2013 Oct 8.
Triterpenoids are a large class of naturally occurring compounds, and some potentially interesting as anticancer agents have been found to target mitochondria. The objective of the present work was to investigate the mechanisms of mitochondrial toxicity induced by novel dimethylaminopyridine (DMAP) derivatives of pentacyclic triterpenes, which were previously shown to inhibit the growth of melanoma cells in vitro. MCF-7, Hs 578T and BJ cell lines, as well as isolated hepatic mitochondria, were used to investigate direct mitochondrial effects. On isolated mitochondrial hepatic fractions, respiratory parameters, mitochondrial transmembrane electric potential, induction of the mitochondrial permeability transition (MPT) pore and ion transport-dependent osmotic swelling were measured. Our results indicate that the DMAP triterpenoid derivatives lead to fragmentation and depolarization of the mitochondrial network in situ, and to inhibition of uncoupled respiration, induction of the permeability transition pore and depolarization of isolated hepatic mitochondria. The results show that mitochondrial toxicity is an important component of the biological interaction of DMAP derivatives, which can explain the effects observed in cancer cells.
三萜类化合物是一大类天然存在的化合物，一些具有潜在抗癌活性的化合物已被发现靶向线粒体。本研究的目的是研究新型二甲氨基吡啶（DMAP）衍生物对五环三萜的线粒体毒性作用机制，先前的研究表明这些衍生物能抑制体外黑色素瘤细胞的生长。MCF-7、Hs 578T 和 BJ 细胞系以及分离的肝线粒体用于研究直接的线粒体效应。在分离的肝线粒体部分，测量呼吸参数、线粒体跨膜电势、诱导线粒体通透性转换（MPT）孔和离子转运依赖性渗透肿胀。我们的结果表明，DMAP 三萜衍生物导致线粒体网络原位碎裂和去极化，并抑制解偶联呼吸、诱导通透性转换孔和分离肝线粒体去极化。结果表明，线粒体毒性是 DMAP 衍生物生物相互作用的一个重要组成部分，这可以解释在癌细胞中观察到的作用。
