In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with
cancer, and several classes of
HDAC inhibitors have been found to have potent and specific anticancer activities in preclinical studies. But their precise mechanism of action has not been elucidated. In this study, a novel synthetic inhibitor of HDAC, 3-(4-dimethylamino phenyl)-N-hydroxy-2-propenamide [IN-2001] was examined for its antitumor activity and the underlying molecular mechanisms of any such activity on human
breast cancer cell lines.
IN-2001 effectively inhibited cellular HDAC activity (IC50 = 0.585 nM) in MDA-MB-231 human
breast cancer cells.
IN-2001 caused a significant dose-dependent inhibition of cell proliferation in
estrogen receptor (ER) negative MDA-MB-231 human
breast cancer cells. Cell cycle analysis revealed that the gowth inhibitory effects of
IN-2001 might be attributed to cell cycle arrest at G0/G1 and/or G2/Mphase and subsequent apoptosis in human
breast cancer cells. These events are accompanied by modulating several cell cycle and apoptosis regulatory genes such as CDK inhibitors p21(WAF1) and p27(KIP1)
cyclin D1, and other tumor suppressor genes such as
cyclin D2. Collectively,
IN-2001 inhibited cell proliferation and induced apoptosis in human
breast cancer cells and these findings may provide new therapeutic approaches, combination of
antiestrogen together with a
HDAC inhibitor, in the hormonal
therapy-resistant ER-negative breast
cancers. In summary, our data suggest that this
histone deacetylase inhibitor,
IN-2001, is a novel promising therapeutic agent with potent antitumor effects against human breast
cancers.