Procaspase-3 activation as an anti-cancer strategy: structure-activity relationship of procaspase-activating compound 1 (PAC-1) and its cellular co-localization with caspase-3.
Procaspase-3 activation as an anti-cancer strategy: structure-activity relationship of procaspase-activating compound 1 (PAC-1) and its cellular co-localization with caspase-3.
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DOI：
10.1021/jm900722z
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发表时间：
2009-09-24
影响因子：
7.3
通讯作者：
Hergenrother, Paul J.
中科院分区：
文献类型：
--
作者：
Peterson, Quinn P.;Hsu, Danny C.;Goode, David R.;Novotny, Chris J.;Totten, Ryan K.;Hergenrother, Paul J.
应用于肿瘤学的个性化医疗的目标是识别利用癌细胞中确定的分子缺陷的化合物。据报道，一种称为 procaspase 激活化合物 1 (PAC-1) 的化合物可在体外增强 procaspase-3 的活性，并诱导培养物和小鼠异种移植模型中的癌细胞凋亡。实验证据表明，PAC-1 在体外通过抑制性锌离子螯合激活 procaspase-3。本文描述了 PAC-1 衍生物家族的合成和生物活性，其中关键官能团已被系统地改变。对这些化合物的分析揭示了体外 procaspase-3 激活作用与其诱导培养癌细胞死亡的能力之间存在很强的相关性。重要的是，我们还表明荧光标记的 PAC-1 与癌细胞中的 caspase-3 活性位点共定位。本文提供的数据进一步支持了以下假设：PAC-1 通过直接激活 procaspase-3 诱导癌细胞凋亡，对下一代 procaspase-3 激活化合物的设计和发现具有影响，并揭示了细胞锌的抗凋亡作用。
A goal of personalized medicine as applied to oncology is to identify compounds that exploit a defined molecular defect in a cancerous cell. A compound called procaspase-activating compound 1 (PAC-1) was reported that enhances the activity of procaspase-3 in vitro and induces apoptotic death in cancer cells in culture and in mouse xenograft models. Experimental evidence indicates that PAC-1 activates procaspase-3 in vitro through chelation of inhibitory zinc ions. Described herein is the synthesis and biological activity of a family of PAC-1 derivatives where key functional groups have been systematically altered. Analysis of these compounds reveals a strong correlation between the in vitro procaspase-3 activating effect and their ability to induce death in cancer cells in culture. Importantly, we also show that a fluorescently-labeled version of PAC-1 co-localizes with sites of caspase-3 activity in cancer cells. The data presented herein further bolster the hypothesis that PAC-1 induces apoptosis in cancer cells through the direct activation of procaspase-3, has implications for the design and discovery of next-generation procaspase-3 activating compounds, and sheds light on the anti-apoptotic role of cellular zinc.
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DOI：
10.1016/s0006-291x(02)02017-x
发表时间：
2002-08-30
影响因子：
3.1
作者：
Haase, H;Beyersmann, D
通讯作者：
Beyersmann, D
影响因子：
15
作者：
Charkoudian, Louise K.;Pham, David M.;Franz, Katherine J.
通讯作者：
Franz, Katherine J.
影响因子：
3.8
作者：
Hershko, C;Abrahamov, A;Link, G
通讯作者：
Link, G
影响因子：
5.2
作者：
Huang, Sha;Clark, Ronald J.;Zhu, Lei
通讯作者：
Zhu, Lei
工程二聚体caspase-9：重新评估caspase激活的诱导接近模型。
影响因子：
9.8
作者：
Chao, Y;Shiozaki, EN;Srinivasula, SM;Rigotti, DJ;Fairman, R;Shi, YG
通讯作者：
Shi, YG