1802

Background/Aims: It is suggested that histone acetylation has an important role in regulating gene expression by alteration of chromatic structure. Histone deacetylase (HDAC) inhibitors have been shown to be effective in suppressing the growth of a variety of cancer cell lines by alteration of chromatic structure and regulating gene expression. Recently, novel hybrid synthetic HDAC inhibitors were built from hydroaxamic acid of trichostatin A (TSA) and pyridyl ring of MS-275 in Korea. In the present study, we examined the apoptosis and cell cycle arrest inducing potential of SK-7041 and dissected cell cycle pathway in pancreatic cell lines. Methods: We evaluated the antiproliferative effects by MTS assay and apoptosis and cell cycle analysis was performed with a FACScan flow cytometer in two pancreatic cancer cell lines (Panc-1 and MiaPaca-2) with TSA and SK-7041. Western blot analyses of cyclin B1, cyclin D2, cyclin E, p21 and caspase-3 were performed using specific antibody to identify the mechanism of cell cycle arrest and confirm the apoptosis. Results: TSA (0.2-2 μM) and SK-7041 (0.5-5 μM) exhibited potent antiproliferative effects and induced G2-M cell cycle arrest and apoptosis at micromolar concentrations dose-dependently. Cycloheximide (CHX) markedly inhibited HDAC inhibitor-induced apoptosis and cell cycle arrest and it means de nevo protein synthesis is required for the initiation of apoptosis and cell cycle arrest. HDAC inhibitors increased the levels of acetylated histone H4 and activated caspase-3 in both cell lines. The expression of p21 and cyclin D2 was up-regulated and that of cyclin B1 was down-regulated by TSA or SK-7041 which was inhibited by CHX. Conclusion: These results suggest that SK-7041 and TSA induce apoptosis and cell cycle arrest related to the regulation of p21, cyclin D2 and cyclin B1 gene expression. SK-7041 is expected to promising anticancer agents and need additional clinical studies.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]