Novel Synthetic Oxazines Target NF-κB in Colon Cancer In Vitro and Inflammatory Bowel Disease In Vivo.
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.
Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College campus, Bangalore-560001, India.
Anilkumar C
AC
Nirvanappa
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore-570005, India.|Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore-570005, India.
Chakrabhavi Dhananjaya
CD
Mohan
Frontier Research Center for Post-Genome Science and Technology, Hokkaido University, Sapporo 0600808, Japan.
Shobith
S
Rangappa
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore-570005, India.
Hanumappa
H
Ananda
N.D. Zelinsky Institute of Organic Chemistry, Leninsky Prospect, 47, Moscow 119991, Russia.
Alexey Yu
AY
Sukhorukov
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117 597, Singapore, Singapore.
Muthu K
MK
Shanmugam
Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysore-570005, India.
Mahalingam S
MS
Sundaram
Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysore-570005, India.
Siddaiah Chandra
SC
Nayaka
Department of Studies in Biochemistry, University of Mysore, Manasagangotri, Mysore-570005, India.
Kesturu S
KS
Girish
Department of Botany and Microbiology, College of Science, King Saud University, Riyadh -11451, Kingdom of Saudi Arabia.
Arunachalam
A
Chinnathambi
Department of Botany and Microbiology, College of Science, King Saud University, Riyadh -11451, Kingdom of Saudi Arabia.
M E
ME
Zayed
Department of Botany and Microbiology, College of Science, King Saud University, Riyadh -11451, Kingdom of Saudi Arabia.
Sulaiman Ali
SA
Alharbi
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117 597, Singapore, Singapore.
Gautam
G
Sethi
Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College campus, Bangalore-560001, India.
Basappa
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore-570005, India.
Kanchugarakoppal S
KS
Rangappa
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