Procaspase-activating compound 1 induces a caspase-3-dependent cell death in cerebellar granule neurons.
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.
Aziz
Gulzeb
G
Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Norway.
Akselsen
Øyvind W
ØW
Hansen
Trond V
TV
Paulsen
Ragnhild E
RE
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism*; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D002642:Chick Embryo; D006835:Hydrazones / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D015032:Zinc / Q000378:metabolism; D019287:Zinc Sulfate / Q000494:pharmacology
C514579:(4-benzylpiperazin-1-yl)acetic acid (3-allyl-2-hydroxybenzylidene)hydrazine; D000970:Antineoplastic Agents; D006835:Hydrazones; D010879:Piperazines; D019287:Zinc Sulfate; D053148:Caspase 3; D015032:Zinc