Procaspase-activating compound 1 induces a caspase-3-dependent cell death in cerebellar granule neurons

Toxicology and Applied Pharmacology
Gulzeb AzizRagnhild E Paulsen

Abstract

Procaspase-activating compound 1, PAC-1, has been introduced as a direct activator of procaspase-3 and has been suggested as a therapeutic agent against cancer. Its activation of procaspase-3 is dependent on the chelation of zinc. We have tested PAC-1 and an analogue of PAC-1 as zinc chelators in vitro as well as their ability to activate caspase-3 and induce cell death in chicken cerebellar granule neuron cultures. These neurons are non-dividing, primary cells with normal caspase-3. The results reported herein show that PAC-1 chelates zinc, activates procaspase-3, and leads to caspase-3-dependent cell death in neurons, as the specific caspase-3-inhibitor Ac-DEVD-cmk inhibited both the caspase-3 activity and cell death. Thus, chicken cerebellar granule neurons is a suitable model to study mechanisms of interference with apoptosis of PAC-1 and similar compounds. Furthermore, the present study also raises concern about potential neurotoxicity of PAC-1 if used in cancer therapy.

Citations

Jul 22, 2014·Biochimica Et Biophysica Acta·Stian SjøliJan-Olof Winberg
Mar 11, 2015·Journal of Cellular and Molecular Medicine·Fangyang WangChunfu Wu
Sep 7, 2011·Biochemical and Biophysical Research Communications·Karen A Boldingh DebernardRagnhild E Paulsen
Aug 5, 2016·Cancer Chemotherapy and Pharmacology·Yanfen ChenQubo Zhu
Apr 11, 2019·Mini Reviews in Medicinal Chemistry·Pelin Çıkla-Süzgün, Ş Güniz Küçükgüzel

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