Profound Chemopreventative Effects of a Hydrogen Sulfide-Releasing NSAID in the APCMin/+ Mouse Model of Intestinal Tumorigenesis.

Mark Paul-Clark,Maxim Freydin,Angela Ianaro,Wagdi Elsheikh,Melissa Chan,Pallavi Devchand,Kyle L Flannigan,John L Wallace,Nicholas Kirkby,Charlotte Cheadle,Terence A Agbor,Jane A Mitchell,Fabio Cominelli

doi:10.1371/journal.pone.0147289

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.

Highlights

Significant progress has been made in the detection, diagnosis and identification of specific molecular mechanisms of colorectal cancer, there is currently no cure for this disease [1]
The predominant form of hereditary cancer in the small and large intestine is known as Familial Associated Polyposis (FAP), which is mainly linked to defects in the Adenomatous Polyposis Coli (APC) gene
We have further evaluated the chemopreventative effects of ATB-346 versus naproxen, using the ApcMin/+ mouse model that closely mimics human FAP [3]

Summary

Introduction

Significant progress has been made in the detection, diagnosis and identification of specific molecular mechanisms of colorectal cancer, there is currently no cure for this disease [1]. The predominant form of hereditary cancer in the small and large intestine is known as Familial Associated Polyposis (FAP), which is mainly linked to defects in the Adenomatous Polyposis Coli (APC) gene. Seventy percent of sporadic colorectal cancers are due to bi-allelic inactivation of the APC gene. APC is a protein involved in the Wnt/β-catenin signaling pathway. Mutations in this signaling pathway are the only known genetic alterations present in early premalignant lesions in the intestine, such as aberrant crypt foci and small adenomas or polyps. Constitutive activation of the Wnt signaling pathway caused by mutations in components of the pathway has been suggested to be responsible for the initiation of colorectal cancer [2]

Methods

Results

Conclusion