Apoptosis induced by novel aldehyde calpain inhibitors in human tumor cell lines.
Apoptosis induced by novel aldehyde calpain inhibitors in human tumor cell lines.
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DOI：
10.3892/ijo.29.3.655
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发表时间：
2006-09
影响因子：
5.2
通讯作者：
Na Guan;Rajani Korukonda;E. Hurh;Thomas D. Schmittgen;I. Donkor;J. Dalton
中科院分区：
文献类型：
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作者：
Na Guan;Rajani Korukonda;E. Hurh;Thomas D. Schmittgen;I. Donkor;J. Dalton
钙蛋白酶是一类Ca（2+）依赖性半胱氨酸蛋白酶，已被认为参与几个重要的信号级联反应。我们实验室鉴定的一系列新型醛类钙蛋白酶抑制剂比市售钙蛋白酶抑制剂更有效和特异，并用于评估钙蛋白酶在癌症中的参与。我们的抑制剂在四种癌细胞系（PC-3、HeLa、Jurkat和Daudi）中表现出有效的抗增殖活性，IC（50）的范围为2至>30 μ M。非癌细胞系（CV-1）的敏感性比癌细胞系低4-7倍。细胞凋亡的活性进行了测定，似乎是负相关的钙蛋白酶的表达水平在不同的细胞类型。白血病细胞系（即，Daudi和Jurkat）与检测不到的m-钙蛋白酶更容易受到钙蛋白酶抑制的凋亡效应的影响，而在PC-3前列腺癌细胞中没有检测到凋亡，其高度表达m-钙蛋白酶。在相同条件下，HeLa细胞的凋亡程度是中等的。钙蛋白酶抑制诱导的细胞凋亡伴随着caspase-3的激活。此外，细胞周期分析表明，醛类钙蛋白酶抑制剂以浓度依赖性方式将细胞阻滞在G2/M期边界。这些结果表明，醛类钙蛋白酶抑制剂通过诱导G2/M期阻滞和细胞凋亡表现出其细胞毒性作用。重要的是，这些化合物未能对20 S蛋白酶体发挥任何抑制作用。总的来说，我们的研究结果表明，钙蛋白酶是一个新的目标，用于治疗各种癌症疾病，并提供线索，进一步发现和开发钙蛋白酶抑制剂。
Calpain is a class of Ca(2+)-dependent cysteine proteases and has been suggested to be involved in several important signaling cascades. A series of novel aldehyde calpain inhibitors identified in our laboratory were more potent and specific than commercially available calpain inhibitors, and were used to assess the involvement of calpain in cancer. Our inhibitors demonstrated potent anti-proliferative activity in four cancer cell lines (PC-3, HeLa, Jurkat and Daudi) with IC(50)'s ranging from 2 to >30 microM. A non-cancer cell line (CV-1) was 4-7-fold less sensitive than the cancer cell lines. Apoptotic activity was determined and appeared to be inversely correlated to calpain expression levels in the different cell types. Leukemia cell lines (i.e., Daudi and Jurkat) with undetectable m-calpain were more susceptible to the apoptotic effects in response to calpain inhibition, while apoptosis was not detected in PC-3 prostate cancer cells, which highly express m-calpain. The extent of apoptosis in HeLa cells was moderate under identical conditions. Apoptosis induced by calpain inhibition was accompanied by caspase-3 activation. Furthermore, cell cycle analysis showed that aldehyde calpain inhibitors arrested cells at the G2/M boundary in a concentration-dependent manner. These results indicate that aldehyde calpain inhibitors exhibit their cytotoxic effects via induction of G2/M arrest and apoptosis. Importantly, the compounds failed to exert any inhibitory effects toward 20S proteasome. Collectively, our results suggest that calpain is a novel target for the treatment of a variety of cancer diseases and provide leads for further discovery and development of calpain inhibitors.