Apoptotic cytotoxic effects of a histone deacetylase inhibitor, FK228, on malignant lymphoid cells

Histone deacetylases are promising targets for cancer treatment. Were we st udied the in vitro effects of a potent histone deacetylase inhibitor, FK228 (formerly FR901228), on human leukemia/ lymphoma cells and cell lines comp ared with normal hematopoietic cells. In a lymphoma cell line, Raji, a nano molar concentration of FK228 induced G1 arrest and/or apoptotic cell death, depending on the concentration and exposure time. Growth of lymphoid cell lines including Raji (N=13) was inhibited by 50% (IC50) after 2-day treatme nt at concentrations of 0.83 to 1.87 ng/ml, Viability of clinical samples f rom patients with acute lymphoblastic leukemia was decreased by 50% at 0.78 +/-0.46 ng/ml, whereas the IC50 values for normal mononuclear cells from pe ripheral blood and bone marrow were 2.3+/-0.96 and 7.8+/-1.0 ng/ml, respect ively. The IC50 values for normal progenitor cells were 3.1, 4.4 and 7.8 ng /ml for BFU-E, CFU-GM and CFU-Mix, respectively. Expression levels of HDAC- 1 and HDAC-3 proteins, which varied among cell lines, but were stable durin g the treatment with FK228, did not correlate with the sensitivity to FK288 , This novel agent might be useful in the treatment of lymphoid malignancie s, because the above concentrations are clinically achievable in vivo accor ding to a recent clinical study.