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

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

Journal

PLOS ONE
ISSN: 1932-6203

Output data

Year: 2016, Volume: 11, Number: 9, Article number : e0163209, Pages count : DOI: 10.1371/journal.pone.0163209

Authors

Nirvanappa Anilkumar C. ¹ , Mohan Chakrabhavi Dhananjaya ^2,3 , Rangappa Shobith ⁴ , Ananda Hanumappa ² , Sukhorukov Alexey Yu. ⁵ , Shanmugam Muthu K. ⁶ , Sundaram Mahalingam S. ⁷ , Nayaka Siddaiah Chandra ⁷ , Girish Kesturu S. ⁷ , Chinnathambi Arunachalam ⁸ , Zayed M.E. ⁸ , Alharbi Sulaiman Ali ⁸ , Sethi Gautam ⁶ , Basappa - ¹ , Rangappa Kanchugarakoppal S. ²

Affiliations

1	Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College campus, Bangalore-560001, India
2	Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore-570005, India
3	Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore-570005, India
4	Frontier Research Center for Post-Genome Science and Technology, Hokkaido University, Sapporo 0600808, Japan
5	N.D. Zelinsky Institute of Organic Chemistry, Leninsky Prospect, 47, Moscow 119991, Russia
6	Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117 597, Singapore, Singapore
7	Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysore-570005, India
8	Department of Botany and Microbiology, College of Science, King Saud University, Riyadh -11451, Kingdom of Saudi Arabia

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.

Nirvanappa A.C. , Mohan C.D. , Rangappa S. , Ananda H. , Sukhorukov A.Y. , Shanmugam M.K. , Sundaram M.S. , Nayaka S.C. , Girish K.S. , Chinnathambi A. , Zayed M.E. , Alharbi S.A. , Sethi G. , Basappa -. , Rangappa K.S.
Novel Synthetic Oxazines Target NF-κB in Colon Cancer In Vitro and Inflammatory Bowel Disease In Vivo
PLOS ONE. 2016. V.11. N9. e0163209 . DOI: 10.1371/journal.pone.0163209 WOS Scopus OpenAlex

Web of science:	WOS:000384328500029
Scopus:	2-s2.0-84991691519
OpenAlex:	W2525431899

DB	Citing
OpenAlex	38
Scopus	38
Web of science	36