The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid and its derivatives elicit human lymphoid cell apoptosis through a novel pathway involving the unregulated mitochondrial permeability transition pore
The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid and its derivatives elicit human lymphoid cell apoptosis through a novel pathway involving the unregulated mitochondrial permeability transition pore
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DOI：
10.1158/0008-5472.can-06-2678
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发表时间：
2007-02-15
期刊：
影响因子：
11.2
通讯作者：
Bernstein, Steven H.
中科院分区：
文献类型：
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作者：
Brookes, Paul S.;Morse, Kimberly;Bernstein, Steven H.
2-氰基-3，12-二氧代齐墩果烷-1，9-二烯-28-酸（CDDO）及其C-28咪唑和二腈衍生物是一类新型的齐墩果烷三萜类化合物，具有良好的抗癌和防癌作用。在此，我们表明，这些三萜类化合物诱导正常和恶性B淋巴细胞凋亡，与C-28衍生物是更有力的比CDDO，通过一种新的线粒体机制。我们使用正常和恶性人类B细胞，以及分离的大鼠线粒体，CDDO直接与有限数量的尚未定义的线粒体蛋白相互作用。这种相互作用导致线粒体巯基状态的丧失和许多线粒体蛋白巯基的二级修饰。我们的数据进一步表明，这样的修饰导致形成高分子量蛋白质聚集体，其形成“不受调节的”、组成型开放的、环孢菌素A不敏感的渗透性转换（PT）孔。这种PT孔的形成导致随后产生线粒体超氧化物和细胞死亡。总之，我们的研究（a）提出了三萜类化合物诱导细胞死亡的新作用机制;（B）是最早直接支持由线粒体蛋白聚集体形成的不受调节的PT孔存在的研究之一，如Lemasters及其同事首次提出的;（c）验证了这种不受调节的PT孔作为开发新癌症疗法的可行靶标。
2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its C-28 imidazole and dinitrile derivatives are novel oleanane triterpenoids exhibiting promise as both therapeutic and preventative agents for cancer. Herein we show that these triterpenoids induce normal and malignant B-lymphoid cell apoptosis, with the C-28 derivatives being more potent than CDDO, through a novel mitochondrial mechanism. We show using both normal and malignant human B Cells, as well as isolated rat mitochondria, that CDDO directly interacts with a limited number of as yet undefined mitochondrial proteins. Such an interaction results in the loss of mitochondrial thiol status and the secondary modification of numerous mitochondrial protein thiols. Our data further suggest that such modifications result in the formation of high molecular weight protein aggregates that form "unregulated'', constitutively open, cyclosporin A-insensitive permeability transition (PT) pores. The formation of such PT pores results in the subsequent generation of mitochondrial superoxide and cell death. In total, our studies (a) suggest a novel mechanism of action for triterpenoid-induced cell death; (b) are among the first to directly support the existence of an unregulated PT pore formed by mitochondrial protein aggregates, as first proposed by Lemasters and colleagues; and (c) validate such an unregulated PT pore as a viable target for the development of new cancer therapeutics.