Apoptosis induced by the histone deacetylase inhibitor sodium butyrate in human leukemic lymphoblasts

The histone deacetylase inhibitor and potential anti-cancer drug sodium but yrate is a general inducer of growth arrest, differentiation, and in certai n cell types, apoptosis. In human CCRF-CEM, acute T lymphoblastic leukemia cells, butyrate, and other histone deacetylase inhibitors caused G2/M cell cycle arrest as well as apoptotic cell death. Forced G0/G1 arrest by tetrac ycline-regulated expression of transgenic p16/INK4A protected the cells fro m butyrate-induced cell death without affecting the extent of histone hyper acetylation, suggesting that the latter may be necessary, but not sufficien t, for cell death induction. Nuclear apoptosis, but not G2/M arrest, was de layed but not prevented by the tripeptide broad-range caspase inhibitor ben zyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD) and, to a lesser exten t, by the tetrapeptide 'effector caspase' inhibitors benzyloxycarbonyl-Asp- Glu-Val-Asp.fluoromethylketone (DEVD) and benzyloxycarbonyl-Val-Glu-Ile-Asp .fluoromethyl-ketone (VEID); however, the viral protein inhibitor of 'induc er caspases', crmA, had no effect. Bcl-2 overexpression partially protected stably transfected CCRF-CEM sublines from butyrate-induced apoptosis, but showed no effect on butyrate-induced growth inhibition, further distinguish ing these two butyrate effects. c-myc, constitutively expressed in CCRF-CEM cells, was down-regulated by butyrate, but this was not causative for cell death. On the contrary, tetracycline-induced transgenic c-myc sensitized s tably transfected CCRF-CEM derivatives to butyrate-induced cell death.-Bern hard, D., Ausserlechner, M. J., Tonko, M., Loffler, M., Hartmann, B. L., Cs ordas, A., Kofler, R. Apoptosis induced by the histone deacetylase inhibito r sodium butyrate in human leukemic lymphoblasts.