Back to Search
Start Over
The histone deacetylase inhibitor MS-275 induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia cells.
- Source :
-
Leukemia [Leukemia] 2004 Jul; Vol. 18 (7), pp. 1207-14. - Publication Year :
- 2004
-
Abstract
- MS-275 is a histone deacetylase (HDAC) inhibitor that has been reported to mediate its cytotoxic effect through generation of reactive oxygen species (ROS) in proliferating hematopoietic cell lines. We examined efficacy of MS-275 in nonproliferating chronic lymphocytic leukemia (CLL) cells from patients. In these cells, MS-275 demonstrated an in vitro LC(50) that was one log lower than for normal mononuclear cells. Following MS-275 treatment, histones H3 and H4 showed increased acetylation and HDAC enzymatic activity was reduced. Caspase-8, -9, and -3 were activated, and caspase substrates PARP and BID were cleaved. Additionally, FLICE-inhibitory protein (FLIP) was downmodulated following MS-275 incubation. MS-275 treatment caused detectable ROS generation after 15 h of incubation, which was blocked by the caspase inhibitor Z-VAD-fmk. Overexpression of Bcl-2 protein protected against MS-275-induced apoptosis. These data demonstrate that MS-275 is a promising therapy for the treatment of CLL, but that in contrast to previous reports, ROS generation does not precede commitment to apoptosis. Similar to many other therapeutic targets, MS-275-mediated apoptosis is reduced by overexpression of Bcl-2, justifying strategies to combine HDAC inhibitors with Bcl-2 antagonists.
- Subjects :
- CASP8 and FADD-Like Apoptosis Regulating Protein
Carrier Proteins metabolism
Caspases metabolism
Enzyme Inhibitors pharmacology
Humans
Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
Leukocytes, Mononuclear drug effects
Leukocytes, Mononuclear pathology
Proto-Oncogene Proteins c-bcl-2 physiology
Reactive Oxygen Species metabolism
Tumor Cells, Cultured
Apoptosis drug effects
Benzamides pharmacology
Histone Deacetylase Inhibitors
Intracellular Signaling Peptides and Proteins
Leukemia, Lymphocytic, Chronic, B-Cell pathology
Pyridines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0887-6924
- Volume :
- 18
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Leukemia
- Publication Type :
- Academic Journal
- Accession number :
- 15116122
- Full Text :
- https://doi.org/10.1038/sj.leu.2403388