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. ©2016 AACR.