Histone deacetylase inhibitors induce growth arrest and apoptosis of HTLV-1-infected T-cells via blockade of signaling by nuclear factor kappaB.

Abstract

Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive disease with a poor prognosis in which nuclear factor kappa B (NF-kappaB) is thought to play a role. This study explored the effects of histone deacetylase inhibitors (HDACIs) MS-275, suberoylanilide hydroxamic acid (SAHA), and LBH589 on both human T-cell lymphotropic virus type I (HTLV-1)-infected T cells (MT-1, -2, -4, and HUT102) and freshly isolated ATL cells harvested from patients. HDACIs effectively inhibited the proliferation of these cells. For example, MS-275, SAHA, and LBH589 effectively inhibited the proliferation of MT-1 cells with ED(50s) of 6microM, 2.5microM, and 100nM, respectively, as measured by 3-(4,5-dimethylithiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay on day 2 of culture. In addition, HDACIs induced cell cycle arrest at the G2/M phase and apoptosis of HTLV-1-infected T-cells in conjunction with regulation of apoptosis-related proteins. Electrophoretic mobility shift assay showed that exposure of HTLV-1-infected T-cells to HDACIs for 48h inhibited formation of the NF-kappaB/DNA binding complex. Moreover, we found that HDACIs accumulated NF-kappaB and inhibitory subunit of NF-kappaB in the cytoplasm in conjunction with the down-regulation of NF-kappaB in the nucleus, suggesting that HDACIs blocked nuclear translocation of NF-kappaB. Based on these findings, we believe HDACIs can be useful for treating patients with ATL or other types of cancer in which NF-kappaB plays a role.

• Authors: Chie Nishioka, Takayuki Ikezoe, Jing Yang, Naoki Komatsu, Kentaro Bandobashi, Ayuko Taniguchi, Yoshio Kuwayama, Kazuto Togitani, H Phillip Koeffler, Hirokuni Taguchi
• Journal: Leukemia research (Leuk Res) Vol. 32 Issue 2 Pg. 287-96 (Feb 2008) ISSN: 0145-2126 [Print] England
• PMID: 17644177 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Indoles
• NF-kappa B
• Pyridines
• entinostat
• Vorinostat
• Panobinostat

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Benzamides (pharmacology)
• Blotting, Western
• Cell Line
• Cell Proliferation (drug effects)
• Deltaretrovirus Infections (drug therapy)
• Electrophoretic Mobility Shift Assay
• Enzyme Inhibitors (pharmacology)
• Flow Cytometry
• Histone Deacetylase Inhibitors
• Human T-lymphotropic virus 1
• Humans
• Hydroxamic Acids (pharmacology)
• Immunohistochemistry
• Indoles
• Leukemia-Lymphoma, Adult T-Cell (drug therapy)
• NF-kappa B (drug effects)
• Panobinostat
• Pyridines (pharmacology)
• Signal Transduction (drug effects)
• Vorinostat