Prevention of Colitis and Colitis-Associated Colorectal Cancer by a Novel Polypharmacological Histone Deacetylase Inhibitor

Abstract

Purpose: Colorectal cancer is a worldwide cancer with rising annual incidence. Inflammation is a well-known cause of colorectal cancer carcinogenesis. Metabolic inflammation (metaflammation) and altered gut microbiota (dysbiosis) have contributed to colorectal cancer. Chemoprevention is an important strategy to reduce cancer-related mortality. Recently, various polypharmacologic molecules that dually inhibit histone deacetylases (HDAC) and other therapeutic targets have been developed.Experimental Design: Prevention for colitis was examined by dextran sodium sulfate (DSS) mouse models. Prevention for colorectal cancer was examined by azoxymethane/dextran sodium sulfate (AOM/DSS) mouse models. Immunohistochemical staining was utilized to analyze the infiltration of macrophages and neutrophils and COX-II expression in mouse tissue specimens. The endotoxin activity was evaluated by Endotoxin Activity Assay Kit.Results: We synthesized a statin hydroxamate that simultaneously inhibited HDAC and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR). Its preventive effect on colitis and colitis-associated colorectal cancer in mouse models was examined. Oral administration of this statin hydroxamate could prevent acute inflammation in the DSS-induced colitis and AOM/ DSS-induced colorectal cancer with superior activity than the combination of lovastatin and SAHA. It also reduced proinflammatory cytokines, chemokines, expression of COX-II, and cyclin D1 in inflammation and tumor tissues, as well as decreasing the infiltration of macrophages and neutrophils in tumor-surrounding regions. Stemness of colorectal cancer and the release of endotoxin in AOM/DSS mouse models were also attenuated by this small molecule.Conclusions: This study demonstrates that the polypharmacological HDAC inhibitor has promising effect on the chemoprevention of colorectal cancer, and serum endotoxin level might serve as a potential biomarker for its chemoprevention. Clin Cancer Res; 22(16); 4158-69. Ó2016 AACR.

Dietary Salt Administration Decreases Enterotoxigenic Bacteroides fragilis (ETBF)-Promoted Tumorigenesis via Inhibition of Colonic Inflammation

“…Results showed that the ETBF-infected AOM/DSS mice given HSD (8%) exhibited significantly decreased polyp numbers compared to the ETBF-infected AOM/DSS mice given NSD ( Figure 5B,C). As previously reported, increased colon inflammation is positively associated with reduced colon length and increased spleen weight in the colitis-promoted tumorigenesis model [31,32]. Consistent with this observation, HSD (8%) + ETBF/AOM/DSS mice showed an increase in colon length ( Figure 5D) and a decrease in spleen weight ( Figure 5E) compared to NSD + ETBF/AOM/DSS mice.…”

Widespread protein lysine acetylation in gut microbiome and its alterations in patients with Crohn’s disease

“…Although further studies are still needed to understand whether the decrease of protein Kac levels may contribute to the depletion of SCFA producers or not in CD patients, the findings in this study indicate that lysine acetylation might be a potential target for manipulating the growth and functional activity of SCFA producers, and thereby for the treatment of diseases such as CD. Accordingly, previous studies have shown that lysine deacetylase (KDAC) inhibitors, such as butyrate, suberyolanilide hydroxamic acid (SAHA), valproic acid (VPA), and statin hydroxamate, effectively treat colitis in animal models [50][51][52][53] . In particular, Wei et al reported that statin hydroxamate alleviated colitis and reduced the blood endotoxin (lipopolysaccharide) level 51 , an indicator of dysbiosis of gut microbiota 54 .…”

Deep characterization of the protein lysine acetylation in human gut microbiome and its alterations in patients with Crohn’s disease

“…Previous studies have shown that various KDAC inhibitors, such as butyrate, suberyolanilide hydroxamic acid (SAHA), valproic acid (VPA) and statin hydroxamate, effectively treat colitis in animal models [38–41]. In particular, Wei et al reported that statin hydroxamate alleviated colitis and reduced the blood endotoxin (lipopolysaccharide) level [39], an indicator of dysbiosis of gut microbiota [42]. Although the mechanism has been attributed to their beneficial effects on the intestinal epithelium cells, our findings indicate that the KDAC inhibitors may in part directly interact with the microbiome for the alleviation of intestinal colitis.…”