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Histone Deacetylase Inhibitor M344 Inhibits Cell Proliferation and Induces Apoptosis in Human THP-1 Leukemia Cells

Department of Internal medicine and Karmanos Cancer Institute, Wayne State University School of Medicine, 550 E. Canfield, Detroit, MI 48201.

¹Current address: Department of Pathology, Wayne State University School of Medicine
*Corresponding author

Dr. Ben Chen

Department of Internal medicine and Karmanos Cancer Institute

Wayne State University School of Medicine

550 E. Canfield

Detroit, MI 48201

E-Mail: chenb@karmanos.org

Abstract

Histone acetylation plays an important role in the silencing and activation of genes involved in tumoregenesis. Trichostatin A, originally identified as an anti-fungal drug, is a potent inhibitor of histone deacetylase (HDAC) with potential anti-tumor activity. In this study, we investigated the effect of M344, an amide analogues of trichostatin A, on the growth and differentiation of THP-1 human leukemia cells. We showed that at low doses, (< 0.2 µM), M344 could inhibit the growth of THP-1 cells at G1 phase in vitro with low cytotoxic effect. Low dose of M344 exerted some differentiating effect on THP-1 cells as judged by the expression of c-fms proto-oncogene (M-CSF receptor) and appearance of adherent cells. Growth arrest induced by M344 is associated with increased levels of cyclin–dependent protein kinase inhibitor p21 and cyclin E, in agreement with G1 phase arrest.  At higher doses (2 µM), M344 could induce THP-1 cells to undergo apoptosis, which was associated with the cleavage of PARP, cytochrome c release and activation of both caspases-8, -9, followed by the activation of caspase-3. In addition, M344 could increase the levels of pro-apoptotic protein Bax but decreased the levels of anti-apoptotic protein XIAP. M344 is a potent activator of NF-kB transcription factor. RT-PCR assay showed that the M344 could transiently increase IL-1 expression yet markedly decreased TNF-a expression. Our results show that M344 is a potent growth inhibitor and inducer of apoptosis in human leukemia cells and suggest potential therapeutic strategies of HDAC inhibitors for patients with leukemias.  

Keywords:  apoptosis; cell cycle; differentiation; histone deacetylase inhibitor; leukemia; M344.

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