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The histone deacetylase inhibitor suberic bishydroxamate regulates the expression of multiple apoptotic mediators and induces mitochondria-dependent apoptosis of melanoma cells.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2004 Apr; Vol. 3 (4), pp. 425-35. - Publication Year :
- 2004
-
Abstract
- Histone deacetylase (HDAC) inhibitors have attracted much interest because of their ability to arrest cell growth, induce cell differentiation, and in some cases, induce apoptosis of cancer cells. In the present study, we have examined a new HDAC inhibitor, suberic bishydroxamate (SBHA), for its effect on a panel of human melanoma cell lines. We report that it induces varying degrees of apoptosis in the melanoma lines but not in melanocytes and fibroblasts. Induction of apoptosis was caspase dependent and was associated with induction of changes in mitochondrial membrane permeability, which could be inhibited by overexpression of Bcl-2. The changes in mitochondria were independent of caspase activation and were associated with changes in conformation of Bax. SBHA down-regulated several key antiapoptotic proteins including X-linked inhibitor of apoptosis and the Bcl-2 family proteins, Bcl-XL and Mcl-1. In contrast, it induced up-regulation of the Bcl-2 family proapoptotic proteins, Bim, Bax, and Bak. In addition, SBHA induced relocation of the protein Bim to mitochondria and its association with Bcl-2. De novo protein synthesis was required for initiation of apoptosis in that the protein synthesis inhibitor, cycloheximide, inhibited SBHA-induced conformational changes in Bax as well as changes in mitochondrial membrane permeability and activation of caspase-3. These results suggest that SBHA induces apoptosis by changing the balance between proapoptotic and antiapoptotic proteins in melanoma cells. The protein Bim may be a key initiator of apoptosis in cells treated with SBHA.
- Subjects :
- Amino Acid Chloromethyl Ketones pharmacology
Apoptosis Regulatory Proteins
Bcl-2-Like Protein 11
Carrier Proteins metabolism
Caspase 3
Caspase Inhibitors
Caspases metabolism
Cell Line, Tumor
Cysteine Proteinase Inhibitors pharmacology
Histone Deacetylases metabolism
Humans
Intracellular Membranes metabolism
Membrane Proteins metabolism
Mitochondria drug effects
Myeloid Cell Leukemia Sequence 1 Protein
Neoplasm Proteins metabolism
Oligopeptides pharmacology
Permeability drug effects
Protein Conformation drug effects
Protein Transport drug effects
Proteins metabolism
Proto-Oncogene Proteins metabolism
Proto-Oncogene Proteins c-bcl-2 chemistry
Proto-Oncogene Proteins c-bcl-2 metabolism
X-Linked Inhibitor of Apoptosis Protein
bcl-2 Homologous Antagonist-Killer Protein
bcl-2-Associated X Protein
bcl-X Protein
Apoptosis drug effects
Enzyme Inhibitors pharmacology
Histone Deacetylase Inhibitors
Hydroxamic Acids pharmacology
Melanoma pathology
Mitochondria metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1535-7163
- Volume :
- 3
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 15078986