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.

• Authors: Tzu-Tang Wei, Yi-Ting Lin, Ruo-Yu Tseng, Chia-Tung Shun, Yu-Chin Lin, Ming-Shiang Wu, Jim-Min Fang, Ching-Chow Chen
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 22 Issue 16 Pg. 4158-69 (Aug 15 2016) ISSN: 1557-3265 [Electronic] United States
• PMID: 27528734 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Cytokines
• Histone Deacetylase Inhibitors
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Inflammation Mediators
• Dextran Sulfate

Topics

• Animals
• Biopsy
• Chemoprevention
• Colitis (chemically induced, complications, pathology, prevention & control)
• Colorectal Neoplasms (etiology, pathology, prevention & control)
• Cytokines (genetics, metabolism)
• Dextran Sulfate (adverse effects)
• Disease Models, Animal
• Gene Expression
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Inflammation Mediators (metabolism)
• Male
• Mice
• Models, Biological
• Neoplastic Stem Cells (metabolism)
• Tumor Burden (drug effects)