Karen Morrison - Differential Effects of Procaspase-3 Activating Compounds in the Induction of Cancer Cell Death

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      Publication Details (including relevant citation   information):

      Mol. Pharmaceutics, 2012, 9 (5), pp 1425–1434


      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 μM), 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.

      Address (URL): http://dx.doi.org/10.1021/mp200673n