A combination of antiapoptotic/antinecroptotic inhibitors protects nccit cells from gamma-irradiation-induced cell death.
Huang-Z; Greenberger-J; Kagan-V; Bayir-H
Toxicologist 2012 Mar; 126(Suppl 1):441
Irradiation-induced cell death includes apoptotic and necroptotic (or programmed necrosis) pathways. Therefore, a search for radiomitigators with the delayed action against acute radiation injury due to radionuclide release in terrorist acts may be based on a combination of antiapoptotic and antinecroptotic inhibitors. Here we used a cocktail that included a pan-capase inhibitor, Z-VAD-fmk, and necrostatin- 1, a specific inhibitor of receptor interacting protein-1 (RIP-1) - a key protein in necroptosis - and assessed their protective effects against irradiation-induced (4 Gy) death of embryonic carcinoma NCCIT cells (5 days after irradiation). We found that a combination of Z-VAD-fmk (50-100 microM) plus necrostatin-1 (20 microM) showed significant radiomitigative effect - from 33.5%-approximately 61.9% in NCCIT cells (treatment at 30 min after the irradiation exposure). No significant protection was afforded by either of these compounds alone. Our results suggest that necroptosis inhibitors - along with other therapeutic modalities - may be promising as mitigators against late radiation-induced cell death.
Cytology; Cell-damage; Cell-morphology; Cellular-function; Laboratory-animals; Molecular-biology; Cell-metabolism; Radiation; Radiation-injury; Pathology; Embryotoxicity; Carcinomas
The Toxicologist. Society of Toxicology 51st Annual Meeting and ToxExpo, March 11-15, 2012, San Francisco, California
University of Pittsburgh at Pittsburgh