1. Profound Chemopreventative Effects of a Hydrogen Sulfide-Releasing NSAID in the APCMin/+ Mouse Model of Intestinal Tumorigenesis
- Author
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Jane A. Mitchell, Nicholas S. Kirkby, Maxim Freydin, Mark J. Paul-Clark, Angela Ianaro, Charlotte Cheadle, Terence A. Agbor, Wagdi Elsheikh, Pallavi Devchand, John L. Wallace, Kyle L. Flannigan, Melissa V. Chan, Paul Clark, Mark, Elsheikh, Wagdi, Kirkby, Nichola, Chan, Melissa, Devchand, Pallavi, Agbor, Terence A., Flannigan, Kyle L., Cheadle, Charlotte, Freydin, Maxim, Ianaro, Angela, Mitchell, Jane A., and Wallace, John L.
- Subjects
0301 basic medicine ,Male ,NSAIDs, cancer, hydrogen sulfide ,Colorectal cancer ,Carcinogenesis ,NSAIDs ,TUMOR-CELLS ,Intestinal polyp ,Cancer Treatment ,lcsh:Medicine ,Pharmacology ,medicine.disease_cause ,COLORECTAL-CANCER ,Transcriptome ,Mice ,0302 clinical medicine ,Naproxen ,Medicine and Health Sciences ,Hydrogen Sulfide ,lcsh:Science ,beta Catenin ,Gastrointestinal tract ,Analgesics ,Multidisciplinary ,biology ,Anti-Inflammatory Agents, Non-Steroidal ,Intestinal Polyps ,Drugs ,Animal Models ,Genomics ,NONSTEROIDAL ANTIINFLAMMATORY DRUGS ,3. Good health ,Gene Expression Regulation, Neoplastic ,Multidisciplinary Sciences ,Oncology ,030220 oncology & carcinogenesis ,Small Intestine ,Science & Technology - Other Topics ,Anatomy ,Transcriptome Analysis ,medicine.drug ,Research Article ,COLITIS ,EXPRESSION ,Colon ,General Science & Technology ,Adenomatous Polyposis Coli Protein ,Mouse Models ,Research and Analysis Methods ,Chemoprevention ,S-SULFHYDRATION ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,Model Organisms ,Intestinal Neoplasms ,ADENOMAS ,MD Multidisciplinary ,medicine ,Genetics ,Animals ,Colitis ,Colorectal Cancer ,Science & Technology ,business.industry ,Gene Expression Profiling ,lcsh:R ,Biology and Life Sciences ,Computational Biology ,Cancers and Neoplasms ,medicine.disease ,Genome Analysis ,GENE ,PREVENTION ,Pain management ,Mice, Inbred C57BL ,Gastrointestinal Tract ,030104 developmental biology ,biology.protein ,lcsh:Q ,Cyclooxygenase ,business ,INHIBITORS ,Digestive System - 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.
- Published
- 2016