Dataset Information

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, ?-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.

SUBMITTER: Paul-Clark M

PROVIDER: S-EPMC4766010 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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

Paul-Clark Mark M Elsheikh Wagdi W Kirkby Nicholas N Chan Melissa M Devchand Pallavi P Agbor Terence A TA Flannigan Kyle L KL Cheadle Charlotte C Freydin Maxim M Ianaro Angela A Mitchell Jane A JA Wallace John L JL

PloS one 20160224 2

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 ...[more]

PMID: 26910063

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Project description:Epigenetic modulators, particularly histone deacetylases (HDACs), are valid targets for cancer prevention and therapy. Recent studies report that HDAC2 overexpression is associated with colon tumor progression and is a potential target for colon cancer prevention. This study tested chemopreventive and dose-response effects of Ohio State University HDAC42 (OSU-HDAC42), a selective HDAC2 inhibitor, using a rat colon carcinogenesis model to assess aberrant crypt foci inhibition and a familial adenomatous polyposis model to assess intestinal tumor inhibition. Colonic aberrant crypt foci were induced by azoxymethane (AOM) (15 mg/kg body weight, once-weekly subcutaneous injections at 8 and 9 weeks age). One week after AOM treatment, groups of rats were fed an AIN-76A diet containing 0, 75, 150, and 300 ppm OSU-HDAC42 for 8 weeks, and colonic aberrant crypt foci were evaluated. To assess the inhibitory effect of OSU-HDAC42 on small-intestinal polyps and colon tumor growth, 6-week-old male C57Bl/6J-APC(min/+)mice were fed an AIN-76A diet containing 150 ppm OSU-HADC42 or 300 ppm pan-HDAC inhibitor suberoylanilide hydroxyamic acid (SAHA) for 80 days. Our results demonstrate that dietary OSU-HDAC42 produced dose-dependent inhibition of AOM-induced colonic aberrant crypt foci formation (13-50%; P < 0.01 to < 0.0001) and reduced multiple crypts with ≥ 4 crypts per focus (25-57%; P < 0.01 to < 0.0001) in F344 rats. Our findings show that 150 ppm OSU-HDAC42 significantly inhibited small-intestinal polyps (>46%; P < 0.001), with polyp size measuring >1 mm (P < 0.001), and colon tumors (>26%) in APC(min/+)mice, whereas 300 ppm SAHA showed nonsignificant inhibition. Mice fed 150 ppm OSU-HDAC42 had significantly decreased HDAC2, proliferating cell nuclear antigen, B cell lymphoma 2, cyclin-dependent kinase 2, and cell division cycle homolog 25C expression levels and increased p53 expression levels. These observations demonstrate the chemopreventive efficacy of OSU-HDAC42 against chemically induced and polyposis models of intestinal tumorigenesis.

Project description:By electrospinning of polycaprolactone (PCL) solutions containing N-(benzoylthio)benzamide (NSHD1), a H2S donor, fibrous scaffolds with hydrogen sulfide (H2S) releasing capability (H2S-fibers) are fabricated. The resultant microfibers are capable of releasing H2S upon immersion in aqueous solution containing biological thiols under physiological conditions. The H2S release peaks of H2S-fibers appeared at 2-4h, while the peak of donor alone showed at 45 min. H2S release half-lives of H2S-fibers were 10-20 times longer than that of donor alone. Furthermore, H2S-fibers can protect cells from H2O2 induced oxidative damage by significantly decreasing the production of intracellular reactive oxygen species (ROS). Finally, we investigated the H2S-fibers application as a wound dressing in vitro. Given that H2S has a broad range of physiological functions, H2S-fibers hold great potential for various biomedical applications.Statement of significanceHydrogen sulfide, as a gaseous messenger, plays a crucial role in many physiological and pathological conditions. Recent studies about functions of H2S suggests H2S-based therapy could be promising therapeutic strategy for many diseases, such as cardiovascular disease, arthritis, and inflammatory bowel disease. Although many H2S donors have been developed and applied for biomedical studies, most of H2S donors have the shortage that the H2S release is either too fast or uncontrollable, which poorly mimic the biological generation of H2S. By simply combining electrospinning technique with our designed biological thiols activated H2S donor, NSHD1, we fabricated H2S releasing microfibers (H2S-fibers). This H2S-fibers significantly prolonged the releasing time compared to H2S donor alone. By adjusting the electrospinning parameters, tunable releasing profiles can be achieved. Moreover, the H2S fibers can protect cardiac myoblasts H9c2 and fibroblast NIH 3T3 from oxidative damage and support their proliferation as cellular scaffolds. To our knowledge, this is the first report of electrospun fibers with H2S releasing capacity. We anticipate this H2S-releasing scaffold will have great potential for biomedical applications.

Dataset Information

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

Publications

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

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