Differential Effects of Procaspase-3 Activating Compounds in the Induction of Cancer Cell Death
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- 作者：Diana C. West ; Yan Qin ; Quinn P. Peterson ; Diana L. Thomas ; Rahul Palchaudhuri ; Karen C. Morrison ; Pamela W. Lucas ; Amy E. Palmer ; Timothy M. Fan ; Paul J. Hergenrother
- 刊名：Molecular Pharmaceutics
- 出版年：2012
- 出版时间：May 7, 2012
- 年：2012
- 卷：9
- 期：5
- 页码：1425-1434
- 全文大小：490K
- 年卷期：v.9,no.5(May 7, 2012)
- ISSN：1543-8392
文摘
The evasion of apoptosis is a key characteristic of cancer, and thus strategies to selectively induce apoptosis in cancer cells hold considerable promise in personalized anticancer therapy. Structurally similar procaspase activating compounds PAC-1 and S-PAC-1 restore procaspase-3 activity through the chelation of inhibitory zinc ions <i>in vitroi>, induce apoptotic death of cancer cells in culture, and reduce tumor burden <i>in vivoi>. Ip or iv administrations of high doses of PAC-1 are transiently neurotoxic <i>in vivoi>, while S-PAC-1 is safe even at very high doses and has been evaluated in a phase I clinical trial of pet dogs with spontaneously occurring lymphoma. Here we show that PAC-1 and S-PAC-1 have similar mechanisms of cell death induction at low concentrations (less than 50 渭M), but at high concentrations PAC-1 displays unique cell death induction features. Cells treated with a high concentration of PAC-1 have a distinctive gene expression profile, unusual cellular and mitochondrial morphology, and an altered intracellular Ca2+ concentration, indicative of endoplasmic reticulum (ER) stress-induced apoptosis. These studies suggest strategies for anticancer clinical development, specifically bolus dosing for PAC-1 and continuous rate infusion for S-PAC-1.