Novel Synthetic Biscoumarins Target Tumor Necrosis Factor-alpha in Hepatocellular Carcinoma in Vitro and in Vivo

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Hosadurga Kumar Keerthy, . and Chakrabhavi Dhananjaya Mohan, . and Kodappully Sivaraman Siveen, . and Julian E. Fuchs, . and Shobith Rangappa, . and Mahalingam, S. and Feng Li, . and Kesturu, . and Girish, S. and Gautam Sethi, . and Basappa, . and Andreas Bender, . and Kanchugarakop, . (2014) Novel Synthetic Biscoumarins Target Tumor Necrosis Factor-alpha in Hepatocellular Carcinoma in Vitro and in Vivo. Journal of Biological Chemistry, 289 (46). pp. 31879-31890. ISSN 1083-351X

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Official URL: https://doi.org/10.1074/jbc.M114.593855

Abstract

Background: TNF--induced NF-B pathway is associated with the progression of several cancers and abrogation of TNF signaling a potential target for cancer treatment. Results: Novel biscoumarin inhibits TNF signaling in vitro and in vivo in IBD model. Conclusion: The lead compound interrupts the trimeric structure of TNF to achieve this effect. Significance: This study introduces a novel TNF inhibitor with the potential to target pro-inflammatory diseases. TNF is a pleotropic cytokine known to be involved in the progression of several pro-inflammatory disorders. Many therapeutic agents have been designed to counteract the effect of TNF in rheumatoid arthritis as well as a number of cancers. In the present study we have synthesized and evaluated the anti-cancer activity of novel biscoumarins in vitro and in vivo. Among new compounds, BIHC was found to be the most cytotoxic agent against the HepG2 cell line while exhibiting less toxicity toward normal hepatocytes. Furthermore, BIHC inhibited the proliferation of various hepatocellular carcinoma (HCC) cells in a dose- and time-dependent manner. Subsequently, using in silico target prediction, BIHC was predicted as a TNF blocker. Experimental validation was able to confirm this hypothesis, where BIHC could significantly inhibit the recombinant mouse TNF- binding to its antibody with an IC50 of 16.5 m. Furthermore, in silico docking suggested a binding mode of BIHC similar to a ligand known to disrupt the native, trimeric structure of TNF, and also validated with molecular dynamics simulations. Moreover, we have demonstrated the down-regulation of p65 phosphorylation and other NF-B-regulated gene products upon BIHC treatment, and on the phenotypic level the compound shows inhibition of CXCL12-induced invasion of HepG2 cells. Also, we demonstrate that BIHC inhibits infiltration of macrophages to the peritoneal cavity and suppresses the activity of TNF- in vivo in mice primed with thioglycollate broth and lipopolysaccharide. We comprehensively validated the TNF- inhibitory efficacy of BIHC in an inflammatory bowel disease mice model.

Item Type: Article
Uncontrolled Keywords: Cancer Therapy; Cell Invasion; Hepatocellular Carcinoma; Inflammatory Bowel Disease (IBD); NF-kappa B (NF-KB); Tumor Necrosis Factor (TNF) NF-KAPPA-B; MODE-OF-ACTION; TNF-ALPHA; BIOLOGICAL EVALUATION; RHEUMATOID-ARTHRITIS; FORCE-FIELD; CANCER; CURCUMIN; PATHWAY; INHIBITION
Subjects: Faculty of Science > Pure Sciences > Chemistry
Divisions: Jnana Bharathi / Central College Campus > Department of Chemistry
Depositing User: Mr H.G. Srikanth
Date Deposited: 22 Oct 2016 06:11
Last Modified: 22 Oct 2016 06:11
URI: http://eprints-bangaloreuniversity.in/id/eprint/6771

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