Novel synthetic biscoumarins target tumor necrosis factor-α in hepatocellular carcinoma in vitro and in vivo

Kumar Keerthy, H. and Mohan, C. D. and Siveen, K. S. and Fuchs, J. E. and Rangappa, S. and Sundaram, M. S. and Li, F. and Girish, K. S. and Sethi, G. and Basappa and Bender, A. 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). pp. 31879-31890. ISSN 0021-9258

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Abstract

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 doseand 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 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 phos-phorylation and other NF-KB-regulated gene products upon BIHC treatment, and on the phenotypic level the compound shows inhibition of CXCLF2-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. © 2014 by I he American bociety tor Biochemistry and Molecular Biology, Inc.

Item Type:	Article
Uncontrolled Keywords:	3, animal experiment, animal model, antineoplastic activity, antineoplastic agent, Article, concentration response, controlled study, human, human cell, IC50, in vitro study, in vivo study, mouse, nonhuman, unclassified drug, animal, Animals, chemistry, drug structure, Humans, animal tissue, drug mechanism, metabolism, molecular docking, Molecular Docking Simulation, molecular dynamics, Anti-Inflammatory Agents, antiinflammatory activity, antiinflammatory agent, drug design, Drug Design, immunoglobulin enhancer binding protein, protein phosphorylation, transcription factor RelA, binding affinity, Cell culture, liver cell, hepatocellular carcinoma cell line, surface plasmon resonance, Surface Plasmon Resonance, Anticancer activities, Diseases, nuclear magnetic resonance spectroscopy, inflammation, signal transduction, Signal Transduction, Experimental validations, Inflammation, Binding energy, Animal, disease model, Disease Models, Mice, Carcinoma, Coumarins, protein binding, coumarin derivative, drug effects, drug protein binding, NF-kappa B, Cytokines, tumor necrosis factor alpha, Hepatocytes, Magnetic Resonance Spectroscopy, protein cleavage, mitosis inhibition, Protein Binding, Molecular dynamics, Tumor Necrosis Factor-alpha, Tumor necrosis factors, Hepatocellular, Hepatocellular carcinoma, Liver Neoplasms, 3' (2 butyl 5 chloro 1h imidazol 4 yl)methylenebis(4 hydroxy 2h chromen 2 one), biscoumarin derivative, colitis, cyclin D1, cytokine, etanercept, Hep G2 Cells, heparin, HepG2 cell line, inflammatory bowel disease, Inflammatory bowel disease, Inflammatory Bowel Diseases, Inflammatory disorders, Inhibitory Concentration 50, Macrophages, Mammals, migration inhibition, Molecular dynamics simulations, nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase, protein mcl 1, Rheumatoid arthritis, salazosulfapyridine, tumor necrosis factor alpha inhibitor
Subjects:	C Chemical Science > Biochemistry C Chemical Science > Chemistry
Divisions:	Department of > Biochemistry Department of > Chemistry
Depositing User:	Arshiya Kousar Library Assistant
Date Deposited:	27 Jun 2019 07:18
Last Modified:	27 Jun 2019 07:20
URI:	http://eprints.uni-mysore.ac.in/id/eprint/3671

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