Open AccessIn vivo Effects of a Histone Deacetylase Inhibitor, FK228, on Human Acute Promyelocytic Leukemia in NOD /Shi‐ scid/scid Mice
Author(s) -
Kosugi Hiroshi,
Ito Masafumi,
Yamamoto Yukiya,
Towatari Masayuki,
Ito Mamoru,
Ueda Ryuzo,
Saito Hidehiko,
Naoe Tomoki
Publication year - 2001
Publication title -
japanese journal of cancer research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 0910-5050
DOI - 10.1111/j.1349-7006.2001.tb01126.x
Subject(s) - trichostatin a , acute promyelocytic leukemia , histone deacetylase inhibitor , depsipeptide , histone deacetylase , nod , cancer research , tretinoin , retinoic acid , in vivo , biology , leukemia , pharmacology , histone , immunology , cell culture , biochemistry , genetics , microbiology and biotechnology , gene
Histone acetylation and deacetylation are closely linked to transcriptional activation and repression, respectively. In acute promyelocytic leukemia (APL), histone deacetylase inhibitors (HDACIs) have a synergistic effect with all‐iraws retinoic acid (ATRA) in vitro to induce differentiation. Here we report in vitro and in vivo effects of a HDACI, FK228 (formerly FR901228 or depsipeptide), on the human APL cell line NB4. FK228 had a strong and irreversible cytotoxicity compared with another HDACI, trichostatin A. In vivo administration of ATRA or FK228 alone partly inhibited the growth of established tumors of NB4 subcutaneously transplanted in NOD/Shi‐scid/scid mice, and the combination was synergistically effective. Histopathological examination revealed that the combination induced apoptosis and differentiation as well as histone acetylation. Intravenous injection of NB4 in NOD/Shi‐scid/scid mice followed by combination treatment significantly prevented leukemia death, whereas single administration did not. These findings suggest that FK228 is a promising agent to enhance ATRA‐sensitivity in the treatment of APL.