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 cancerassociated
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 antiinflammatory
drug that potently and rapidly prevents and reverses the development of precancerous
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.