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.
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.
Mori
Naoki
N
Division of Molecular Virology and Oncology, Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215, Japan. n-mori@med.u-ryukyu.ac.jp
Matsuda
Takehiro
T
Tadano
Masayuki
M
Kinjo
Takao
T
Yamada
Yasuaki
Y
Tsukasaki
Kunihiro
K
Ikeda
Shuichi
S
Yamasaki
Yoshihiro
Y
Tanaka
Yuetsu
Y
Ohta
Takao
T
Iwamasa
Teruo
T
Tomonaga
Masao
M
Yamamoto
Naoki
N
D000328:Adult; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002461:Cell Line, Transformed; D047630:Depsipeptides; D004195:Disease Models, Animal; D015536:Down-Regulation; D056572:Histone Deacetylase Inhibitors; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects; D006801:Humans; D015458:Leukemia, T-Cell / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000821:virology*; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D016328:NF-kappa B; D010456:Peptides, Cyclic; D018808:Transcription Factor AP-1; C087123:romidepsin