A novel small-molecule activator of procaspase-3 induces apoptosis in cancer cells and reduces tumor growth in human breast, liver and gallbladder cancer xenografts
A novel small-molecule activator of procaspase-3 induces apoptosis in cancer cells and reduces tumor growth in human breast, liver and gallbladder cancer xenografts
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一种新型小分子 procaspase-3 激活剂诱导癌细胞凋亡并减少人乳腺癌、肝癌和胆囊癌异种移植物中的肿瘤生长
DOI：
10.1016/j.molonc.2014.06.015
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发表时间：
2014-12-01
影响因子：
6.6
通讯作者：
Wu, Chunfu
中科院分区：
文献类型：
--
作者：
Wang, Fangyang;Wang, Lihui;Wu, Chunfu
目的：Procaspase-3是凋亡执行者caspase-3的酶原，在许多肿瘤中过表达。我们的目的是表征一种新的procaspase-3激活剂，WF-210，这可能是一个潜在的抗癌drug.Experimental设计：在体外和体内，使用正常细胞，癌细胞，小鼠异种移植模型的procaspase-3激活能力，抗肿瘤疗效，作用机制，和毒性档案的WF-210进行了研究。结果：WF-210激活caspase-3的EC_（50）为0.95 μ M，小于其母体化合物PAC-1（2.08 μ M）的一半。该机制涉及抑制性锌离子的螯合，随后导致半胱氨酸蛋白酶原-3的自动激活。WF-210对人癌细胞的细胞毒作用强于PAC-1，但对正常细胞的细胞毒作用弱于PAC-1。具有高procaspase-3表达的癌细胞，如HL-60和U-937，特别敏感。WF-210通过激活半胱氨酸蛋白酶前体，促进蛋白酶体依赖的XIAP和Survivin降解，诱导HL-60和U-937细胞凋亡。WF-210诱导细胞凋亡的程度与caspase-3的表达水平有关。最后，WF-210在延缓过表达半胱天冬酶原-3的乳腺、肝脏和胆囊异种移植肿瘤的体内生长方面上级PAC-1，并且不诱导实质性体重减轻或神经毒性。WF-210和PAC-1对不表达procaspase-3的MCF-7异种移植瘤的生长没有影响。结论：WF-210是一种有效的procaspase-3小分子激活剂。WF-210良好的抗肿瘤活性和可接受的毒性特征为其在高半胱氨酸天冬氨酸蛋白酶原-3表达肿瘤治疗中的临床评价提供了强有力的理论基础。(C)2014年欧洲生物化学学会联合会。Elsevier B. V.出版，保留所有权利。
Purpose: Procaspase-3, a proenzyme of apoptotic executioner caspase-3, is overexpressed in numerous tumors. We aimed to characterize a novel procaspase-3 activator, WF-210, which may have potential as an anticancer drug.Experimental design: The procaspase-3 activating ability, antitumor efficacy, mechanisms of action, and toxicity profiles of WF-210 were investigated in vitro and in vivo, using normal cells, cancer cells, and mouse xenograft models. The role of procaspase-3 in WF-210induced apoptosis was explored by manipulating procaspase-3 expression in cultured cells.Results: WF-210 activated procaspase-3 with an EC50 of 0.95 mu M, less than half that of its mother compound PAC-1 (2.08 mu M). The mechanism involved the chelation of inhibitory zinc ions, subsequently resulting in an auto-activation of procaspase-3. WF-210 was more cytotoxic than PAC-1 to human cancer cells, but less cytotoxic to normal cells. Cancer cells with high procaspase-3 expression, like HL-60 and U-937, were particularly sensitive. WF-210-induced the apoptosis of HL-60 and U-937 cells by activating procaspases and promoting proteasome-dependent degradation of XIAP and Survivin. The level of WF-210induced apoptosis in cultured cells was related to the level of procaspase-3 expression. Finally, WF-210 was superior to PAC-1 in retarding the in vivo growth of breast, liver and gallbladder xenograft tumors which overexpress procaspase-3, and induced no substantial weight loss or neurotoxicity. WF-210 and PAC-1 had no effect on the growth of MCF-7 xeno-graft tumors, which do not express procaspase-3.Conclusion: We identified WF-210 as a potent small-molecule activator of procaspase-3. The favorable antitumor activity and acceptable toxicity profile of WF-210 provide a strong rationale for its clinical evaluation in the treatment of tumors with high procaspase-3 expression. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.