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Institute for General and Experimental Pathology, Division of Molecular Pathophysiology; and
* Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Medical School, Innsbruck, Austria, A-6020
1Correspondence: Institute for General and Experimental Pathology, Division of Molecular Pathophysiology, Fritz-Pregl-Straße 3, A-6020 Innsbruck, Austria. E-mail: Reinhard.Kofler{at}uibk.ac.at
The histone deacetylase inhibitor and potential anti-cancer drug sodium butyrate is a general inducer of growth arrest, differentiation, and in certain 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 tetracycline-regulated expression of transgenic p16/INK4A protected the cells from butyrate-induced cell death without affecting the extent of histone hyperacetylation, suggesting that the latter may be necessary, but not sufficient, for cell death induction. Nuclear apoptosis, but not G2/M arrest, was delayed but not prevented by the tripeptide broad-range caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp·fluoromethylketone (zVAD) and, to a lesser extent, 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 `inducer 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 distinguishing 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 stably transfected CCRF-CEM derivatives to butyrate-induced cell death.—Bernhard, D., Ausserlechner, M. J., Tonko, M., Löffler, M., Hartmann, B. L., Csordas, A., Kofler, R. Apoptosis induced by the histone deacetylase inhibitor sodium butyrate in human leukemic lymphoblasts.
Key Words: caspase • c-myc • bcl-2 • p16/INK4A • CCRF-CEM
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