Apoptosis induced by the histone deacetylase inhibitor sodium butyrate in human leukemic lymphoblasts.
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
D
Institute for General and Experimental Pathology, Division of Molecular Pathophysiology, Institute of Medical Chemistry, University of Innsbruck, Innsbruck, Austria, A-6020.
Ausserlechner
M J
MJ
Tonko
M
M
Löffler
M
M
Hartmann
B L
BL
Csordas
A
A
Kofler
R
R
D017209:Apoptosis / Q000187:drug effects*; D002087:Butyrates / Q000494:pharmacology*; D020169:Caspases / Q000502:physiology; D002460:Cell Line; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects; D016259:Genes, myc / Q000502:physiology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology*; D008938:Mitosis / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology
D002087:Butyrates; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D020169:Caspases