Cytoprotective effect of selective small-molecule caspase inhibitors against staurosporine-induced apoptosis.
Cytoprotective effect of selective small-molecule caspase inhibitors against staurosporine-induced apoptosis.
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DOI：
10.2147/dddt.s60283
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Ma H
中科院分区：
文献类型：
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作者：
Wu J;Wang Y;Liang S;Ma H
半胱天冬酶是目前已知的凋亡途径的中央执行者。通过半胱天冬酶抑制剂抑制细胞凋亡和促进正常细胞存活对于减少癌症治疗的副作用和控制神经退行性疾病如帕金森病、阿尔茨海默病和亨廷顿病将是巨大的益处。本研究的目的是寻找具有细胞保护作用的小分子半胱天冬酶抑制剂。我们完成了对Bionet的37，500种化合物库（Key Organics Limited，Camelford，Cornwall，UK）针对caspase-1，-3和-9的高通量筛选，并成功鉴定了43种初始命中化合物。进一步测试了43种命中化合物在NIH 3 T3细胞中针对星形孢菌素诱导的细胞死亡的细胞保护活性。在细胞活力测定中发现19种化合物具有显著的细胞保护作用。其中一种化合物RBC 1023被证明可以保护NIH 3 T3细胞免受星形孢菌素诱导的caspase-3切割和激活。RBC 1023还显示出保护免于星形孢菌素诱导的线粒体膜电位的损害。DNA微阵列分析表明，星形孢菌素治疗诱导广泛的全球基因表达的变化，和RBC 1023共同治疗显着恢复这些变化，特别是与细胞生长和生存信号，如Egr 1，Cdc 25 c，cdkn 3，Rhob，Nek 2和Taok 1相关的基因。RBC 1023通过抑制caspase活性、恢复线粒体膜电位、上调细胞存活相关基因表达和通路，保护NIH 3 T3细胞免受星形孢菌素诱导的凋亡。
Caspases are currently known as the central executioners of the apoptotic pathways. Inhibition of apoptosis and promotion of normal cell survival by caspase inhibitors would be a tremendous benefit for reducing the side effects of cancer therapy and for control of neurodegenerative disorders such as Parkinson’s, Alzheimer’s, and Huntington’s diseases. The objective of this study was to discover small-molecule caspase inhibitors with which to achieve cytoprotective effect. We completed the high-throughput screening of Bionet’s 37,500-compound library (Key Organics Limited, Camelford, Cornwall, UK) against caspase-1, -3, and -9 and successfully identified 43 initial hit compounds. The 43 hit compounds were further tested for cytoprotective activity against staurosporine-induced cell death in NIH3T3 cells. Nineteen compounds were found to have significant cytoprotective effects in cell viability assays. One of the compounds, RBC1023, was demonstrated to protect NIH3T3 cells from staurosporine-induced caspase-3 cleavage and activation. RBC1023 was also shown to protect against staurosporine-induced impairment of mitochondrial membrane potential. DNA microarray analysis demonstrated that staurosporine treatment induced broad global gene expression alterations, and RBC1023 co-treatment significantly restored these changes, especially of the genes that are related to cell growth and survival signaling such as Egr1, Cdc25c, cdkn3, Rhob, Nek2, and Taok1. Collectively, RBC1023 protects NIH3T3 cells against staurosporine-induced apoptosis via inhibiting caspase activity, restoring mitochondrial membrane potential, and possibly upregulating some cell survival-related gene expressions and pathways.