期刊
JOURNAL OF INVESTIGATIVE DERMATOLOGY
卷 125, 期 5, 页码 1045-1052出版社
ELSEVIER SCIENCE INC
DOI: 10.1111/j.0022-202X.2005.23925.x
关键词
apoptosis; cutaneous T cell lymphoma; histone deacetylase inhibitor
类别
资金
- NCI NIH HHS [CA 16672, K24-CA 86815, R21-CA 74117] Funding Source: Medline
Suberoylanilide hydroxamic acid (SAHA), an orally administered inhibitor of histone deacetylases, is currently in phase II clinical trials for cutaneous T cell lymphomas (CTCL), but the mechanism of SAHA action is unknown. In this study, we investigated the anti-tumor effects of SAHA in CTCL cell lines and freshly isolated peripheral blood lymphocytes (PBL) from CTCL patients with high percentage of circulating malignant T cells. Three cell lines (MJ, Hut78, and HH) and PBL from 11 patients and three healthy donors were treated with SAHA (1, 2.5, and 5 mu M) for 24 and/or 48 h. Apoptosis was determined by flow cytometry analysis of sub-G, hypodiploid nuclei and/or annexin V binding populations. Acetylated histones and apoptosis-associated proteins were detected by Western blotting. SAHA at 1-5 mu M for 24 and 48 h induced apoptosis in a concentration- and time-dependent manner in three cell lines: MJ (0%-7% and 1%-32%), Hut78 (4%-36% and 5%-54%), and HH (4%-67% and 8%-81%). SAHA at 1-5 mu M for 48 h also induced more apoptosis of patients' PBL than healthy donors' (15%-32% versus 6%-13%, p<0.05). SAHA treatment caused an accumulation of acetylated histones (H2B, H3, and H4), an increase of p21(WAF1) and bax proteins, a decrease of Stat6 and phospho-Stat6 proteins, and activation of caspase-3 in CTCL cells. Our data suggest that selective induction of malignant T cell apoptosis and modulation of acetylated histones, p21(WAF1), bax, Stat6, and caspase-3 may underlie the therapeutic action of SAHA in CTCL patients.
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