gw9662 and Cell-Transformation--Neoplastic

Colitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease (IBD), resulting from long-term inflammation in the intestines. The primary cause of CAC is the imbalance of oxidative metabolism in intestinal cells, triggered by excessive reactive oxygen (ROS) and nitrogen (NO) species production due to prolonged intestinal inflammation. This imbalance leads to genomic instability caused by DNA damage, eventually resulting in the development of intestinal cancer. Previous studies have demonstrated that astragaloside IV is effective in treating dextran sulfate sodium salt (DSS)-induced colitis, but there is currently no relevant research on its efficacy in treating CAC.. To investigate the effect of astragaloside IV against CAC and the underlying mechanism, C57 mice were treated with (20, 40, 80 mg/kg) astragaloside IV while CAC was induced by intraperitoneal injection of 10 mg/kg azoxymethane (AOM) and ad libitum consumption of 2% dextran sulfate sodium salt (DSS). We re-verified the activating effects of astragaloside IV on PPARγ signaling in IEC-6 cells, which were reversed by GW9662 (the PPARγ inhibitor).. Our results showed that astragaloside IV significantly improved AOM/DSS-induced CAC mice by inhibiting colonic shortening, preventing intestinal mucosal damage, reducing the number of tumors and, the expression of Ki67 protein. In addition, astragaloside IV could activate PPARγ signaling, which not only promoted the expression of Nrf2 and HO-1, restored the level of SOD, CAT and GSH, but also inhibited the expression of iNOS and reduced the production of NO in the intestine and IEC-6 cells. And this effect could be reversed by GW9662 in vitro. Astragaloside IV thus decreased the level of ROS and NO in the intestinal tract of mice, as well as reduced the damage of DNA, and therefore inhibited the occurrence of CAC.. Astragaloside IV can activate PPARγ signaling in intestinal epithelial cells and reduces DNA damage caused by intestinal inflammation, thereby inhibiting colon tumourigenesis. The novelty of this study is to use PPARγ as the target to inhibit DNA damage to prevent the occurrence of CAC.

Topics: Animals; Azoxymethane; Carcinogenesis; Cell Transformation, Neoplastic; Colitis; Dextran Sulfate; Disease Models, Animal; Inflammation; Mice; Mice, Inbred C57BL; PPAR gamma; Reactive Oxygen Species

Prostate cancer (PCa) is the most commonly diagnosed cancer in men in the Western Countries. When prostatectomy fails to eradicate the primary tumor, PCa is generally refractory to all therapeutic approaches. Valproic acid (VPA) is a promising anticancer agent recently assigned to the class of histone deacetylase (HDAC) inhibitors. However molecular mechanisms underlying VPA action in PCa cells are largely unknown and further experimental validation to prove its potential application in clinic practice is needed.. In our study we show that VPA is a potent inducer of neuro-endocrine transdifferentiation (NET) in androgen receptor null PCa cells, both in vitro and in vivo. NET was an early event detectable through the expression of neuro-endocrine (NE) markers within 72 hr after VPA treatment and it was associated to a reduction in the overall cell proliferation. When we interrupted VPA treatment we observed the recovery in residual cells of the basal proliferation rate both in vitro and in a xenograft model. The NET process was related to Bcl-2 over-expression in non-NE PCa cells and to the activation of PPARgamma in NE cells. The use of specific PPARgamma antagonist was able to reduce significantly the expression of NE markers induced by VPA.. Our data indicate that the use of VPA as monotherapy in PCa has to be considered with extreme caution, since it may induce an unfavorable NET. In order to counteract the VPA-induced NET, the inhibition of PPARgamma may represent a suitable adjuvant treatment strategy and awaits further experimental validation.

Topics: Adenocarcinoma; Anilides; Animals; Cell Line, Tumor; Cell Proliferation; Cell Transdifferentiation; Cell Transformation, Neoplastic; Drug Combinations; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Humans; Male; Mice; Mice, Nude; Neurosecretory Systems; PPAR gamma; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Valproic Acid; Xenograft Model Antitumor Assays