title: Profound Chemopreventative Effects of a Hydrogen Sulfide-Releasing NSAID in the APCMin/+ Mouse Model of Intestinal Tumorigenesis.
abstract: Nonsteroidal anti-inflammatory drugs have been shown to reduce the incidence of gastrointestinal cancers, but the propensity of these drugs to cause ulcers and bleeding limits their use. H2S has been shown to be a powerful cytoprotective and anti-inflammatory substance in the digestive system. This study explored the possibility that a H2S-releasing nonsteroidal anti-inflammatory drug (ATB-346) would be effective in a murine model of hereditary intestinal cancer (APCMin+ mouse) and investigated potential mechanisms of action via transcriptomics analysis. Daily treatment with ATB-346 was significantly more effective at preventing intestinal polyp formation than naproxen. Significant beneficial effects were seen with a treatment period of only 3-7 days, and reversal of existing polyps was observed in the colon. ATB-346, but not naproxen, significantly decreased expression of intestinal cancer-associated signaling molecules (cMyc, β-catenin). Transcriptomic analysis identified 20 genes that were up-regulated in APCMin+ mice, 18 of which were reduced to wild-type levels by one week of treatment with ATB-346. ATB-346 is a novel, gastrointestinal-sparing anti-inflammatory drug that potently and rapidly prevents and reverses the development of pre-cancerous lesions in a mouse model of hereditary intestinal tumorigenesis. These effects may be related to the combined effects of suppression of cyclooxygenase and release of H2S, and correction of most of the APCMin+-associated alterations in the transcriptome. ATB-346 may represent a promising agent for chemoprevention of tumorigenesis in the GI tract and elsewhere.
authors.affiliation: Imperial College London, London, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Paul-Clark
authors.affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Wagdi
authors.initials: W
authors.lastname: Elsheikh
authors.affiliation: Imperial College London, London, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kirkby
authors.affiliation: William Harvey Research Institute, London, United Kingdom.
authors.forename: Melissa
authors.initials: M
authors.lastname: Chan
authors.affiliation: Mount Sinai Hospital, Icahn Medical Institute, New York, United States of America.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Devchand
authors.affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Terence A
authors.initials: TA
authors.lastname: Agbor
authors.affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Flannigan
authors.affiliation: Imperial College London, London, United Kingdom.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Cheadle
authors.affiliation: Imperial College London, London, United Kingdom.
authors.forename: Maxim
authors.initials: M
authors.lastname: Freydin
authors.affiliation: Department of Experimental Pharmacology, Universita di Napoli Federico II, Napoli, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Ianaro
authors.affiliation: Imperial College London, London, United Kingdom.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Mitchell
authors.affiliation: Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, Canada.|Faculty of Medicine, Universidade Camilo Castelo Branco, São Paulo, SP, Brazil.
authors.forename: John L
authors.initials: JL
authors.lastname: Wallace
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000627:therapeutic use; D063646:Carcinogenesis / Q000187:drug effects*; D018890:Chemoprevention; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006862:Hydrogen Sulfide / Q000737:chemistry*; D007414:Intestinal Neoplasms / Q000473:pathology* / Q000517:prevention & control*; D007417:Intestinal Polyps / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009288:Naproxen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C550692:2-(6-methoxy-napthalen-2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester; D025601:Adenomatous Polyposis Coli Protein; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016271:Proto-Oncogene Proteins c-myc; D051176:beta Catenin; D009288:Naproxen; D006862:Hydrogen Sulfide