Apoptosis induced by the histone deacetylase inhibitor FR901228 in human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells.

Abstract

Inhibition of histone deacetylase (HDAC) activity induces growth arrest, differentiation, and, in certain cell types, apoptosis. FR901228, FK228, or depsipeptide, is an HDAC inhibitor effective in T-cell lymphomas. Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1) and remains incurable. We examined whether FR901228 is effective for treatment of ATL by assessing its ability to induce apoptosis of HTLV-1-infected T-cell lines and primary leukemic cells from ATL patients. FR901228 induced apoptosis of Tax-expressing and -unexpressing HTLV-1-infected T-cell lines and selective apoptosis of primary ATL cells, especially those of patients with acute ATL. FR901228 also efficiently reduced the DNA binding of NF-kappaB and AP-1 in HTLV-1-infected T-cell lines and primary ATL cells and down-regulated the expression of Bcl-x(L) and cyclin D2, regulated by NF-kappaB. Although the viral protein Tax is an activator of NF-kappaB and AP-1, FR901228-induced apoptosis was not associated with reduced expression of Tax. In vivo use of FR901228 partly inhibited the growth of tumors of HTLV-1-infected T cells transplanted subcutaneously in SCID mice. Our results indicated that FR901228 could induce apoptosis of these cells and suppress the expression of NF-kappaB and AP-1 and suggest that FR901228 could be therapeutically effective in ATL.

• Authors: Naoki Mori, Takehiro Matsuda, Masayuki Tadano, Takao Kinjo, Yasuaki Yamada, Kunihiro Tsukasaki, Shuichi Ikeda, Yoshihiro Yamasaki, Yuetsu Tanaka, Takao Ohta, Teruo Iwamasa, Masao Tomonaga, Naoki Yamamoto
• Journal: Journal of virology (J Virol) Vol. 78 Issue 9 Pg. 4582-90 (May 2004) ISSN: 0022-538X [Print] United States
• PMID: 15078940 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Antibiotics, Antineoplastic
• Depsipeptides
• Histone Deacetylase Inhibitors
• NF-kappa B
• Peptides, Cyclic
• Transcription Factor AP-1
• romidepsin

Topics

• Adult
• Animals
• Antibiotics, Antineoplastic (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Line, Transformed
• Depsipeptides
• Disease Models, Animal
• Down-Regulation
• Histone Deacetylase Inhibitors
• Human T-lymphotropic virus 1 (drug effects)
• Humans
• Leukemia, T-Cell (drug therapy)
• Mice
• Mice, SCID
• NF-kappa B (drug effects, metabolism)
• Peptides, Cyclic (pharmacology, therapeutic use)
• T-Lymphocytes (virology)
• Transcription Factor AP-1 (drug effects, metabolism)
• Tumor Cells, Cultured