Anti-cancer effect of N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2,3-dihydronaphtho[1,2-b]furan-2-carboxamide, a novel synthetic compound

摘要

Naphthofuran compounds have been known to regulate HNF 4 which is associated with proliferation, progression and metastasis of HCC. In this study, we investigated whether N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2,3-dihydronaphtho[1,2-b]furan-2-carboxamide (NHDC), a novel synthetic naphthofuran compound inhibits liver tumor growth through activation of HNF 4. Treatment with different concentrations (1-10.8 mu M) of NHDC for various periods (0-72h) inhibited liver cancer cells (HepG2, Hep3B) growth as well as colony formation followed by induction of apoptosis in a concentration dependent manner. NHDC also induced expression of the apoptosis regulating genes as well as inhibiting the action of STAT3. These inhibitory effects were associated with enhancement of expression and DNA binding activity of HNF 4. In vivo study confirmed that liver tumor growth was prevented with NHDC (5mg/kg), and its effect was also related with inhibition of STAT3 pathway through enhancement of expression and DNA binding activity of HNF 4. Moreover, siRNA of HNF 4 abolished NHDC-induced cell growth inhibition as well as DNA binding activity and phosphorylation of STAT3. Pull down assay docking prediction analysis proved that NHDC directly binds to hydrophobic fatty acid ligand binding site of HNF 4. A novel naphthofuran compound, NHDC inhibited liver tumor growth by inactivating of STAT3 through direct biding to HNF 4. (c) 2015 Wiley Periodicals, Inc.