Poly(ADP-ribose) polymerase inhibition modulates experimental acute necrotizing pancreatitis-induced oxidative stress, bacterial translocation and neopterin concentrations in rats.

Various studies have been performed to find out novel treatment strategies for acute necrotizing pancreatitis (ANP). Inhibition of poly(ADP-ribose) polymerase (PARP) is shown to reduce inflammation in several pathological conditions. We aimed to evaluate the efficacy of benzamide, a PARP inhibitor, in an experimental model of ANP. Thirty Sprague-Dawley rats were divided into three groups: sham-operated, ANP and ANP + benzamide groups. All groups except the sham-operated group were subjected to the ANP procedure, induced by infusing of 1 mL/kg of 3% sodium taurocholate into the common biliopancreatic duct. The ANP + benzamide group received 100 mg/kg/day benzamide intraperitoneally for a total of three days after induction of pancreatitis. The surviving animals were killed at the fourth day and the pancreas was harvested for biochemical, microbiological and histological analysis. Blood samples were also obtained from the animals. In the ANP group, a significant increase was observed in concentrations of serum amylase and neopterin and tissue oxidative stress indices (malondialdehyde, superoxide dismutase and glutathione peroxidase). Almost all of these changes were found to be reversed to near their normal values in the ANP + benzamide group. Histological injury scores were significantly higher in the ANP group than in the sham group (P < 0.05, ANP versus sham), and were significantly lower in the ANP + benzamide group than in the ANP group (P < 0.05, ANP + benzamide versus ANP). Evaluation of bacterial translocation identified significantly fewer infected sites in the ANP + benzamide group than in the ANP animals (P < 0.01). We observed that inhibition of PARP with benzamide reduced the severity, the mortality, the bacterial translocation rates and the neopterin concentrations in an experimental ANP model in rats. These findings suggest that it may be possible to improve the outcome of ANP by using PARP inhibitors.

CRA-026440: a potent, broad-spectrum, hydroxamic histone deacetylase inhibitor with antiproliferative and antiangiogenic activity in vitro and in vivo.

CRA-026440 is a novel, broad-spectrum, hydroxamic acid-based inhibitor of histone deacetylase (HDAC) that shows antitumor and antiangiogenic activities in vitro and in vivo preclinically. CRA-026440 inhibited pure recombinant isozymes HDAC1, HDAC2, HDAC3/SMRT, HDAC6, HDAC8, and HDAC10 in the nanomolar range. Treatment of cultured tumor cell lines grown in vitro with CRA-026440 resulted in the accumulation of acetylated histone and acetylated tubulin, leading to an inhibition of tumor cell growth and the induction of apoptosis. CRA-026440 inhibited ex vivo angiogenesis in a dose-dependent manner. CRA-026440 parenterally given to mice harboring HCT116 or U937 human tumor xenografts resulted in a statistically significant reduction in tumor growth. CRA-026440, when used in combination with Avastin, achieved greater preclinical efficacy in HCT 116 colorectal tumor model. Inhibition of tumor growth was accompanied by an increase in the acetylation of alpha-tubulin in peripheral blood mononuclear cells and an alteration in the expression of many genes in the tumors, including several involved in angiogenesis, apoptosis, and cell growth. These results reveal CRA-026440 to be a novel HDAC inhibitor with potent antitumor activity.