Procaspase-activating compound 1 induces a caspase-3-dependent cell death in cerebellar granule neurons
Journal Article
·
· Toxicology and Applied Pharmacology
- Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo (Norway)
- Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo (Norway)
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.
- OSTI ID:
- 21460211
- Journal Information:
- Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 247; ISSN TXAPA9; ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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