title: Calpain-2 Inhibitor Therapy Reduces Murine Colitis and Colitis-associated Cancer.
abstract: BACKGROUND
  An important role has emerged for calpain enzymes in regulating inflammation with one isoform, calpain-2, particularly important for macrophage activation. The goal of this study was to determine the therapeutic potential of a synthetic calpain-2 inhibitor, zLLY-CH2F, for colitis and inflammation-associated colorectal cancer.
  
  
  METHODS
  Mice were then subjected to the azoxymethane/dextran sulfate sodium model of colitis and colitis-associated cancer incorporating intervention with daily injections of 0.75 mg/kg calpain-2 inhibitor beginning after the first signs of colitis.
  
  
  RESULTS
  Calpain-2 inhibitor treatment alleviated weight loss and bloody diarrhea, and reduced inflammatory infiltration into colon tissues and inflammatory cytokine mRNA. Calpain-2 inhibitor intervention also reduced total colitis-associated cancer tumor volume by up to 70% in vehicle control mice and decreased cancer pathology scores of blinded histological colon tissue analyses. Mechanistic investigations showed that calpain-2 inhibition during macrophage activation reduced inhibitor of kappa beta (IκB) degradation and nuclear factor kappa beta (NFκB) nuclear localization as well as secretion of specific inflammatory cytokines. In addition, calpain-2 inhibitor treatment of CT26.WT mouse and HT-29 human colorectal cancer cells decreased proliferation and reduced IκB degradation and NFκB translocation.
  
  
  CONCLUSIONS
  Overall, these findings suggest that intervention with a calpain-2 inhibitor may reduce colitis and colitis-associated cancer through a two-hit process of limiting macrophage activation and inhibiting growth of the colorectal cancer cells themselves.
authors.affiliation: *Department of Cellular and Molecular Biology, John A. Burns School of Medicine, Honolulu, Hawaii; †Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, China; and ‡Department of Pathology, John A. Burns School of Medicine, Honolulu, Hawaii.
authors.forename: Aaron H
authors.initials: AH
authors.lastname: Rose
authors.forename: Zhi
authors.initials: Z
authors.lastname: Huang
authors.forename: Chrisy
authors.initials: C
authors.lastname: Mafnas
authors.forename: Jared H
authors.initials: JH
authors.lastname: Hara
authors.forename: FuKun W
authors.initials: FW
authors.lastname: Hoffmann
authors.forename: Ann S
authors.initials: AS
authors.lastname: Hashimoto
authors.forename: Pietro
authors.initials: P
authors.lastname: Bertino
authors.forename: Peter R
authors.initials: PR
authors.lastname: Hoffmann
mesh_terms: D000818:Animals; D001397:Azoxymethane; D049109:Cell Proliferation; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D019073:HT29 Cells / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000187:drug effects / Q000235:genetics; D007249:Inflammation / Q000150:complications / Q000473:pathology; D007274:Injections, Intraperitoneal; D008262:Macrophage Activation / Q000187:drug effects*; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology*; D014178:Translocation, Genetic
chemical_list: D016207:Cytokines; D020672:I-kappa B Proteins; D016328:NF-kappa B; D009842:Oligopeptides; C069861:calpain inhibitor 2; D016264:Dextran Sulfate; D001397:Azoxymethane