Novel synthetic oxazines target NF-κB in colon cancer In Vitro and inflammatory bowel disease In Vivo

Anilkumar, C. N. and Mohan, C. D. and Shobith, R. and Ananda, H. and Sukhorukov, Alexey Yu and Muthu K. Shanmugam, and Sundaram, M. S. and Nayaka, S. Chandra and Girish, K. S. and Chinnathambi, A. and Zayed, M. E. and Alharbi, Sulaiman Ali and Sethi, Gautam and Basappa, and Rangappa, K. S. (2016) Novel synthetic oxazines target NF-κB in colon cancer In Vitro and inflammatory bowel disease In Vivo. PLoS One, 11 (9). ISSN 1932-6203

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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 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-κB by oxazines, we evaluated the effect of 1,2-oxazines against the ability of NF-κB binding to DNA, NF-κB-dependent luciferase expression and IκBα phosphorylation. We found that, API abrogate constitutive activation of NF-κB and inhibits IκBα 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 IκBα. Given the relevance with aberrant activation of NF-κB 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-α, IFN-γ, IL-6, IL-1β 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-κB inhibitory efficacy of API that targets NF-κB in in vitro colon cancer and an in vivo inflammatory bowel disease model.

Item Type: Article
Additional Information: Unmapped bibliographic data: M3 - doi:10.1371/journal.pone.0163209 [Field not mapped to EPrints] JA - PLOS ONE [Field not mapped to EPrints]
Subjects: Agriculture Biological Sciences > Biochemistry
University of Mysore > PG Campuses > Manasagangotri, Mysore > Agriculture Biological Sciences > Biochemistry

Physical Sciences > Chemistry
Divisions: PG Campuses > Manasagangotri, Mysore > Biochemistry
PG Campuses > Manasagangotri, Mysore > Chemistry
Depositing User: Praveen Kumari B.L
Date Deposited: 05 Sep 2017 10:36
Last Modified: 05 Sep 2017 10:36

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