In vivo effects of a histone deacetylase inhibitor, FK228, on human acute promyelocytic leukemia in NOD/Shi-scid/scid mice

Histone acetylation and deacetylation are closely linked to transcriptional activation and repression, respectively. Iii acute promyelocytic leukemia (APL), histone deacetylase inhibitors (HDACIs) have a synergistic effect wi th all-trans retinoic acid (ATRA) in vitro to induce differentiation. Here we report ira vitro and ill vivo effects of a HDACI, FK228 (formerly FR9012 28 or depsipeptide), on the human APII cell line NB4. FK228 had a strong an d 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 differentia tion as well as histone acetylation, Intravenous injection of NB4 in NOD/Sh i-scid/scid mice followed by combination treatment significantly prevented leukemia death, whereas single administration did not. These findings sugge st that FK228 is a promising agent to enhance ATRA-sensitivity in the treat ment of APL.