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 in vitro, induce apoptotic death of cancer cells in culture, and reduce tumor burden in vivo. Ip or iv administrations of high doses of PAC-1 are transiently neurotoxic in vivo, 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.