RESUMEN
OBJECTIVES: Inhibition of histone deacetylase activity is one of the epigenetic mechanisms in the regulation of the cellular gene expression. We investigated the antitumor effect of HA-But, a new histone deacetylase inhibitor, in which hyaluronic acid is esterified with butyric acid residues and selectively bind to CD44, overexpressed in most human cancers, including pancreatic cancer. METHODS: We analyzed the effect of HA-But on the expression level of some cell cycle (p21 waf1/cip1, p27 kip1, p53, and cyclin D1), apoptosis (BAX, caspase-7, Bcl-2, and survivin), and angiogenesis-related (vascular endothelial growth factor [VEGF] A165, VEGF-C, and VEGF-D) proteins on MIA PaCa-2, a pancreas carcinoma cell line that expressed CD44 in a high percentage (99%) of cells. RESULTS: HA-But was 7-fold more effective than sodium butyrate in inhibiting cell proliferation; it induced p21 waf1/cip1, p27 kip1, p53, and cyclin D1 modulation, resulting in a block of the cell cycle at G0/G1 and G2/M phases. Moreover, Ha-But induced apoptosis, affecting the expression level of either proapoptotic or antiapoptotic factors, reduced the expression level of VEGF-A165 and VEGF-D, and inhibited the angiogenesis process in vitro. CONCLUSIONS: On the basis of these results, which demonstrated an interesting antiproliferative, proapoptotic, and antiangiogenic activity, Ha-But could be a promising candidate for the treatment of pancreatic cancer.
