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5-azacytidine and decitabine exert proapoptotic effects on neoplastic mast cells: role of FAS-demethylation and FAS re-expression, and synergism with FAS-ligand.
- Source :
-
Blood [Blood] 2012 May 03; Vol. 119 (18), pp. 4242-52. Date of Electronic Publication: 2012 Mar 21. - Publication Year :
- 2012
-
Abstract
- Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) are advanced hematopoietic neoplasms with poor prognosis. In these patients, neoplastic mast cells (MCs) are resistant against various drugs. We examined the effects of 2 demethylating agents, 5-azacytidine and decitabine on growth and survival of neoplastic MCs and the MC line HMC-1. Two HMC-1 subclones were used, HMC-1.1 lacking KIT D816V and HMC-1.2 exhibiting KIT D816V. Both agents induced apoptosis in HMC-1.1 and HMC-1.2 cells. Decitabine, but not 5-azacytidine, also produced a G(2)/M cell-cycle arrest in HMC-1 cells. Drug-induced apoptosis was accompanied by cleavage of caspase-8 and caspase-3 as well as FAS-demethylation and FAS-re-expression in neoplastic MCs. Furthermore, both demethylating agents were found to synergize with the FAS-ligand in inducing apoptosis in neoplastic MCs. Correspondingly, siRNA against FAS was found to block drug-induced expression of FAS and drug-induced apoptosis in HMC-1 cells. Neither 5-azacytidine nor decitabine induced substantial apoptosis or growth arrest in normal MCs or normal bone marrow cells. Together, 5-azacytidine and decitabine exert growth-inhibitory and proapoptotic effects in neoplastic MCs. These effects are mediated through "FAS-re-expression" and are augmented by the FAS-ligand. Whether epigenetic drugs produce antineoplastic effects in vivo in patients with ASM and MCL remains to be determined.
- Subjects :
- Adult
Aged
Base Sequence
Cell Line, Tumor drug effects
CpG Islands
DNA Methylation drug effects
DNA, Neoplasm metabolism
Decitabine
Drug Synergism
Fas Ligand Protein physiology
Female
Humans
Male
Mast Cells pathology
Methylation drug effects
Middle Aged
Molecular Sequence Data
Neoplasm Proteins metabolism
Point Mutation
Promoter Regions, Genetic genetics
Proto-Oncogene Proteins c-kit genetics
RNA, Small Interfering pharmacology
fas Receptor antagonists & inhibitors
fas Receptor genetics
Antimetabolites, Antineoplastic pharmacology
Apoptosis drug effects
Azacitidine analogs & derivatives
Azacitidine pharmacology
Leukemia, Mast-Cell pathology
Mast Cells drug effects
Mastocytosis, Systemic pathology
Protein Processing, Post-Translational drug effects
fas Receptor metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 119
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 22438247
- Full Text :
- https://doi.org/10.1182/blood-2011-09-382770