title: Prevention of Colitis and Colitis-Associated Colorectal Cancer by a Novel Polypharmacological Histone Deacetylase Inhibitor.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Tzu-Tang
authors.initials: TT
authors.lastname: Wei
authors.affiliation: Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Ruo-Yu
authors.initials: RY
authors.lastname: Tseng
authors.affiliation: Graduate Institute of Forensic Medicine, National Taiwan University College of Medicine, Taipei, Taiwan. Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chia-Tung
authors.initials: CT
authors.lastname: Shun
authors.affiliation: Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. Department of Internal Medicine, Far-Eastern Memorial Hospital, New Taipei City, Taiwan.
authors.forename: Yu-Chin
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ming-Shiang
authors.initials: MS
authors.lastname: Wu
authors.affiliation: Department of Chemistry, National Taiwan University, Taipei, Taiwan.
authors.forename: Jim-Min
authors.initials: JM
authors.lastname: Fang
authors.affiliation: Department of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan. chingchowchen@ntu.edu.tw.
authors.forename: Ching-Chow
authors.initials: CC
authors.lastname: Chen
mesh_terms: D000818:Animals; D001706:Biopsy; D018890:Chemoprevention; D003092:Colitis / Q000139:chemically induced / Q000150:complications* / Q000473:pathology / Q000517:prevention & control*; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D015870:Gene Expression; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D016264:Dextran Sulfate