| Molecular sequelae of histone deacetylase inhibition in human malignant B cells. | |
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MedLine Citation:
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PMID: 12531799 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Histone acetylation modulates gene expression, cellular differentiation, and survival and is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC inhibition results in accumulation of acetylated nucleosomal histones and induces differentiation and/or apoptosis in transformed cells. In this study, we characterized the effect of suberoylanilide hydroxamic acid (SAHA), the prototype of a series of hydroxamic acid-based HDAC inhibitors, in cell lines and patient cells from B-cell malignancies, including multiple myeloma (MM) and related disorders. SAHA induced apoptosis in all tumor cells tested, with increased p21 and p53 protein levels and dephosphorylation of Rb. We also detected cleavage of Bid, suggesting a role for Bcl-2 family members in regulation of SAHA-induced cell death. Transfection of Bcl-2 cDNA into MM.1S cells completely abrogated SAHA-induced apoptosis, confirming its protective role. SAHA did not induce cleavage of caspase-8, -9, or -3 in MM.1S cells during the early phase of apoptosis, and the pan-caspase inhibitor ZVAD-FMK did not protect against SAHA. Conversely, poly(ADP)ribose polymerase (PARP) was cleaved in a pattern indicative of calpain activation, and the calpain inhibitor calpeptin abrogated SAHA-induced cell death. Importantly, SAHA sensitized MM.1S cells to death receptor-mediated apoptosis and inhibited the secretion of interleukin 6 (IL-6) induced in bone marrow stromal cells (BMSCs) by binding of MM cells, suggesting that it can overcome cell adhesion-mediated drug resistance. Our studies delineate the mechanisms whereby HDAC inhibitors mediate anti-MM activity and overcome drug resistance in the BM milieu and provide the framework for clinical evaluation of SAHA, which is bioavailable, well tolerated, and bioactive after oral administration, to improve patient outcome. |
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Authors:
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Nicholas Mitsiades; Constantine S Mitsiades; Paul G Richardson; Ciaran McMullan; Vassiliki Poulaki; Galinos Fanourakis; Robert Schlossman; Dharminder Chauhan; Nikhil C Munshi; Teru Hideshima; Victoria M Richon; Paul A Marks; Kenneth C Anderson |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't Date: 2003-01-16 |
Journal Detail:
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Title: Blood Volume: 101 ISSN: 0006-4971 ISO Abbreviation: Blood Publication Date: 2003 May |
Date Detail:
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Created Date: 2003-05-06 Completed Date: 2003-07-18 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 4055-62 Citation Subset: AIM; IM |
Affiliation:
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Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acetylation Apoptosis / drug effects B-Lymphocytes / enzymology* Bone Marrow Cells / enzymology, pathology Cysteine Proteinase Inhibitors / pharmacology Enzyme Inhibitors / pharmacology Histone Deacetylase Inhibitors* Humans Hydroxamic Acids / pharmacology Multiple Myeloma / enzymology, pathology Poly(ADP-ribose) Polymerases / metabolism Tumor Cells, Cultured Waldenstrom Macroglobulinemia / enzymology |
| Chemical | |
Reg. No./Substance:
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0/Cysteine Proteinase Inhibitors; 0/Enzyme Inhibitors; 0/Histone Deacetylase Inhibitors; 0/Hydroxamic Acids; 149647-78-9/vorinostat; EC 2.4.2.30/Poly(ADP-ribose) Polymerases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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