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

Keerthy, H. K. and Mohan, C. D. and Siveen, K. S. and Fuchs, Julian E. and Shobith Rangappa, and Sundaram, M. S. and Feng Li, and Girish, K. S. and Sethi, Gautam and Basappa, and Bender, Andreas and Rangappa, K. S. (2014) Novel Synthetic Biscoumarins Target Tumor Necrosis Factor-α in Hepatocellular Carcinoma in Vitro and in Vivo. Journal of Biological Chemistry, 289 (46). 31879-31890.

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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-α binding to its antibody with an IC50 of 16.5 μm. 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-κB-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-α in vivo in mice primed with thioglycollate broth and lipopolysaccharide. We comprehensively validated the TNF-α inhibitory efficacy of BIHC in an inflammatory bowel disease mice model.

Item Type: Article
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: 18 Feb 2015 11:27
Last Modified: 18 Feb 2015 11:27

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