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Novel Synthetic Oxazines Target NF-?B in Colon Cancer In Vitro and Inflammatory Bowel Disease In Vivo.

ABSTRACT: Aberrant activation of nuclear factor kappa B (NF-?B) has been linked with the pathogenesis of several proinflammatory diseases including number of cancers and inflammatory bowel diseases. In the present work, we evaluated the anticancer activity of 1,2-oxazines derivatives against colorectal cancer cell lines and identified 2-((2-acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-oxazin-3-yl)methyl)isoindoline-1,3-dione (API) as the lead anticancer agent among the tested compounds. The apoptosis inducing effect of API was demonstrated using flow cytometry analysis and measuring the caspase 3/7 activity in API treated cells. Based on the literature on inhibition of NF-?B by oxazines, we evaluated the effect of 1,2-oxazines against the ability of NF-?B binding to DNA, NF-?B-dependent luciferase expression and I?B? phosphorylation. We found that, API abrogate constitutive activation of NF-?B and inhibits I?B? phosphorylation in HCT116 cells. Our in silico analysis revealed the binding of oxazines to the hydrophobic cavity that present between the interface of p65 and I?B?. Given the relevance with aberrant activation of NF-?B in inflammation bowel disease (IBD), we evaluated the effect of API on dextran sulphate sodium-induced IBD mice model. The treatment of IBD induced mice with API decreased the myeloperoxidase activity in colonic extract, modulated the colon length and serum levels of pro- and anti-inflammatory cytokines such as TNF-?, IFN-?, IL-6, IL-1? and IL-10. Furthermore, the histological analysis revealed the restoration of the distorted cryptic epithelial structure of colon in the API treated animals. In conclusion, we comprehensively validated the NF-?B inhibitory efficacy of API that targets NF-?B in in vitro colon cancer and an in vivo inflammatory bowel disease model.

SUBMITTER: Nirvanappa AC

PROVIDER: S-EPMC5042377 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Novel Synthetic Oxazines Target NF-κB in Colon Cancer In Vitro and Inflammatory Bowel Disease In Vivo.

Nirvanappa Anilkumar C AC Mohan Chakrabhavi Dhananjaya CD Rangappa Shobith S Ananda Hanumappa H Sukhorukov Alexey Yu AY Shanmugam Muthu K MK Sundaram Mahalingam S MS Nayaka Siddaiah Chandra SC Girish Kesturu S KS Chinnathambi Arunachalam A Zayed M E ME Alharbi Sulaiman Ali SA Sethi Gautam G Basappa Rangappa Kanchugarakoppal S KS

PloS one 20160929 9

Aberrant activation of nuclear factor kappa B (NF-κB) has been linked with the pathogenesis of several proinflammatory diseases including number of cancers and inflammatory bowel diseases. In the present work, we evaluated the anticancer activity of 1,2-oxazines derivatives against colorectal cancer cell lines and identified 2-((2-acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-oxazin-3-yl)methyl)isoindoline-1,3-dione (API) as the lead anticancer agent among the tested compounds. The apoptosis i ...[more]

PMID: 27685808

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Project description:Inflammatory Bowel Diseases (IBD) are chronic inflammatory disorders, where epithelial defects drive, at least in part, some of the pathology. We reconstituted human intestinal epithelial organ, by using three-dimension culture of human colon organoids. Our aim was to characterize morphological and functional phenotypes of control (non-IBD) organoids, compared to inflamed organoids from IBD patients. The results generated describe the epithelial defects associated with IBD in primary organoid cultures, and evaluate the use of this model for pharmacological testing of anti-inflammatory approaches. Human colonic tissues were obtained from either surgical resections or biopsies, all harvested in non-inflammatory zones. Crypts were isolated from controls (non-IBD) and IBD patients and were cultured up to 12-days. Morphological (size, budding formation, polarization, luminal content), cell composition (proliferation, differentiation, immaturity markers expression), and functional (chemokine and tight junction protein expression) parameters were measured by immunohistochemistry, RT-qPCR or western-blot. The effects of inflammatory cocktail or anti-inflammatory treatments were studied in controls and IBD organoid cultures respectively. Organoid cultures from controls or IBD patients had the same cell composition after 10 to 12-days of culture, but IBD organoid cultures showed an inflammatory phenotype with decreased size and budding capacity, increased cell death, luminal debris, and inverted polarization. Tight junction proteins were also significantly decreased in IBD organoid cultures. Inflammatory cytokine cocktail reproduced this inflammatory phenotype in non-IBD organoids. Clinically used treatments (5-ASA, glucocorticoids, anti-TNF) reduced some, but not all parameters. Inflammatory phenotype is associated with IBD epithelium, and can be studied in organoid cultures. This model constitutes a reliable human pre-clinical model to investigate new strategies targeting epithelial repair.

Dataset Information

Novel Synthetic Oxazines Target NF-?B in Colon Cancer In Vitro and Inflammatory Bowel Disease In Vivo.

Publications

Novel Synthetic Oxazines Target NF-κB in Colon Cancer In Vitro and Inflammatory Bowel Disease In Vivo.

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