title: Inhibition of colon carcinogenesis by 2-methoxy-5-amino-N-hydroxybenzamide, a novel derivative of mesalamine.
abstract: OBJECTIVE
  Mesalamine has been reported to protect against inflammatory bowel disease-related colorectal cancer (CRC), but several drug-related issues have limited its use in chemopreventive programs. We evaluated the antineoplastic properties of mesalamine derivatives using in vitro and in vivo models of CRC.
  
  
  METHODS
  CRC cell proliferation and cell-cycle progression were evaluated by flow cytometry after exposure to mesalamine or mesalamine derivatives. Cyclins, cyclin-dependent kinases, and endoplasmic reticulum stress-related molecules were examined by immunoblotting. The in vivo antineoplastic effect of 2-methoxy-5-amino-N-hydroxybenzamide (2-14) was evaluated in a syngenic, CT26-derived xenograft mouse model of CRC and in the azoxymethane/dextran sulfate sodium-induced mouse model of colitis-associated CRC.
  
  
  RESULTS
  The mesalamine derivative 2-14 was 10-fold more potent than mesalamine in inhibiting CRC cell proliferation. After exposure to 2-14, cyclin D1 expression was reduced and G0/G1 phase cells accumulated. These events were preceded by activation of eukaryotic translation initiation factor 2-alpha kinase 3 (pancreatic endoplasmic reticulum eIF2alpha kinase), phosphorylation of eukaryotic translation initiation factor 2alpha, induction of activating transcription factor 4, and splicing of X-box binding protein 1 messenger RNA, events that define endoplasmic reticulum stress. Silencing of PERK restored cyclin D1 levels, allowing cells to overcome the cell-cycle block induced by 2-14. Mice injected with 2-14 developed fewer CRC xenograft-derived tumors. Moreover, 2-14 injection reduced the development of neoplastic lesions induced by azoxymethane and dextran sulfate sodium in mice.
  
  
  CONCLUSIONS
  The mesalamine derivative 2-14 inhibited CRC cell proliferation in vitro and prevented CRC progression in mouse models.
authors.affiliation: Department of Internal Medicine, University of Tor Vergata, Rome, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Stolfi
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Sarra
authors.forename: Roberta
authors.initials: R
authors.lastname: Caruso
authors.forename: Massimo Claudio
authors.initials: MC
authors.lastname: Fantini
authors.forename: Daniele
authors.initials: D
authors.lastname: Fina
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellegrini
authors.forename: Giampiero
authors.initials: G
authors.lastname: Palmieri
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Macdonald
authors.forename: Francesco
authors.initials: F
authors.lastname: Pallone
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monteleone
mesh_terms: D000636:Aminosalicylic Acids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000494:pharmacology; D001397:Azoxymethane / Q000494:pharmacology; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003092:Colitis / Q000188:drug therapy* / Q000473:pathology*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D019938:Cyclin D1 / Q000378:metabolism; D016264:Dextran Sulfate / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D020868:Gene Silencing; D045325:HCT116 Cells; D006801:Humans; D019804:Mesalamine / Q000737:chemistry; D051379:Mice; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D019892:eIF-2 Kinase / Q000235:genetics
chemical_list: D000636:Aminosalicylic Acids; D016588:Anticarcinogenic Agents; D001397:Azoxymethane; D001549:Benzamides; D002273:Carcinogens; D019938:Cyclin D1; D016264:Dextran Sulfate; D019804:Mesalamine; D019892:eIF-2 Kinase; C547423:2-methoxy-5-amino-N-hydroxybenzamide; C530105:Ccnd1 protein, mouse