Histone deacetylase (HDAC) inhibitors inhibit cell proliferation, induce differentiation and/or apoptotic cell death, and exhibit potent antimetastatic and antiangiogenic properties in cancer cells in vitro and in vivo. Although they are emerging as a promising new treatment strategy in malignancy, how they exert their effect on human leukemic cells is as yet unclear. The present study was undertaken to investigate the underlying mechanism of a HDAC inhibitor trichostatin A (TSA)-induced growth arrest and its effect on the cell cycle control gene products in a human leukemic cell line U937. TSA treatment induced the growth inhibition and morphological changes in a concentration-dependent manner. Treatment of U937 cells with TSA resulted in a concentration-dependent increased G1 cell population of the cell cycle as determined by flow cytometry. Moreover, 75 ng/ml TSA treatment significantly induced the population of apoptotic sub-G1 cells (10.9 fold of control). This anti-proliferative effect of TSA was accompanied by a inhibition of cyclins and proliferating cell nuclear antigen (PCNA), positive regulators of cell cycle progression, and cyclin-dependent kinases (Cdks) expression and concomitant induction of Cdk inhibitors such as p16, p21 and p27. Although further studies are needed, these findings provide important insights into the possible molecular mechanisms of the anti-cancer activity of TSA in human leukemic cells. (Cancer Prev Res 11, 114-122, 2006)

Keywords: Histone deacetylase inhibitor, Trichostatin A, U937 leukemic cells, Cell cycle