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

• DOI: 10.1074/jbc.m114.593855
• Publication Date: 2014-09-18T06:27:47Z
• Authors: Hosadurga Kumar K...; Chakrabhavi Dhana...; Kodappully Sivara...; Julian E. Fuchs; Shobith Rangappa; Mahalingam S. Sun...; Feng Li; Kesturu S. Girish; Gautam Sethi; Basappa; Andreas Bender; Kanchugarakoppal ...
• Keywords: 570; Carcinoma, Hepatocellular; Magnetic Resonance Spectroscopy; Anti-Inflammatory Agents; 610; Biochemistry; Inhibitory Concentration 50; Mice; 03 medical and health sciences; Coumarins; Animals; Humans; Inflammation; 0303 health sciences; Liver Neoplasms; NF-kappa B; Hep G2 Cells; Inflammatory Bowel Diseases; 3. Good health; Molecular Docking Simulation; Chemistry; Disease Models, Animal; Drug Design; Hepatocytes; Cytokines; Protein Binding; Signal Transduction

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