Pyrrolidine dithiocarbamate induces apoptosis by a cytochrome c-dependent mechanism
Pyrrolidine dithiocarbamate induces apoptosis by a cytochrome c-dependent mechanism
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DOI：
10.1006/bbrc.2000.2161
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发表时间：
2000-02-24
影响因子：
3.1
通讯作者：
Zappia, V
中科院分区：
文献类型：
--
作者：
Della Ragione, F;Cucciolla, V;Zappia, V
吡咯烷二硫代氨基甲酸酯(PDTC)是一种人工合成的抗氧化剂，由于其具有诱导细胞凋亡的能力，近年来被认为是一种抗肿瘤药物。我们研究了PDTC对早幼粒细胞系HL-60增殖和存活的影响。低浓度的PDTC可显著降低细胞的生长速度，同时激活细胞的凋亡过程。生化分析证实细胞程序性死亡，包括原天冬氨酸氨基转移酶3的激活和多聚ADP核糖聚合酶(PARP)的裂解。依赖PDTC的细胞凋亡与线粒体早期释放细胞色素c有关，而caspase3和caspase8激活的详细时程分析排除了细胞死亡受体参与的途径。此外，在能够诱导细胞凋亡的PDTC浓度下，p21(CIP1)水平没有上调，p21(CIP1)是一种关键的周期蛋白依赖性激酶抑制物。最后，纯化的线粒体与PDTC的体外孵育表明，该分子能够直接诱导细胞色素c从膜间隙释放，从而证实线粒体是该分子的主要细胞靶点。(C)2000本学术出版社。
Pyrrolidine dithiocarbamate (PDTC) is a synthetic antioxidant molecule, which has been recently proposed as an antitumoral agent on the basis of its capability of inducing apoptosis. We investigated the effect of PDTC on the proliferation and survival of the promyelocitic cell line HL-60. Concentration as low as 10 mu M of PDTC induces a significant reduction of the growth rate and the contemporaneous activation of the apoptotic process. Programmed cell death was demonstrated by biochemical analyses, including the activation of procaspase 3 and the cleavage of poly(ADP-ribose) polymerase (PARP). PDTC-dependent apoptosis was associated with an early release of cytochrome c from mitochondria, while the involvement of pathways due to cell death receptors engagement was ruled out by detailed time-course analyses of caspases 3 and 8 activation. Moreover, no up-regulation of p21(CIP1) level, a pivotal cyclin-dependent kinase inhibitor, occurred at PDTC concentration able to induce apoptosis. Finally, in vitro incubation of purified mitochondria with PDTC demonstrated that the molecule is directly able to induce cytochrome c release from the intermembrane space, thus confirming that mitochondria are a primary cellular target of the molecule. (C) 2000 Academic press.