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.

Abstract

Naphthofuran compounds have been known to regulate HNF 4α 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 4α. Treatment with different concentrations (1-10.8 µM) of NHDC for various periods (0-72 h) 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 4α. In vivo study confirmed that liver tumor growth was prevented with NHDC (5 mg/kg), and its effect was also related with inhibition of STAT3 pathway through enhancement of expression and DNA binding activity of HNF 4α. Moreover, siRNA of HNF 4α 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 4α. A novel naphthofuran compound, NHDC inhibited liver tumor growth by inactivating of STAT3 through direct biding to HNF 4α.

• Authors: Sun Mi Kwon, Yu Yeon Jung, Chul Ju Hwang, Mi Hee Park, Na Young Yoon, Tae Myung Kim, Ji Myung Yu, Dae Hwan Kim, Doo Won Seo, Hyu Seok Youn, Hyun Ok Seo, In Sung Chung, Sang Bae Han, Bang Yeon Hwang, Hwan-Soo Yoo, Jae-Kyung Jung, Heesoon Lee, Jin Tae Hong
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 55 Issue 5 Pg. 659-70 (May 2016) ISSN: 1098-2744 [Electronic] United States
• PMID: 25865242 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 Wiley Periodicals, Inc.

Chemical References

• Antineoplastic Agents
• Furans
• HNF4A protein, human
• Hepatocyte Nuclear Factor 4
• NHDC compound
• Naphthalenes
• Naphthols
• STAT3 Transcription Factor
• STAT3 protein, human

Topics

• Animals
• Antineoplastic Agents (administration & dosage, chemical synthesis, pharmacology)
• Apoptosis
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Furans (administration & dosage, chemical synthesis, pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Hep G2 Cells
• Hepatocyte Nuclear Factor 4 (metabolism)
• Humans
• Liver Neoplasms (drug therapy, metabolism)
• Mice
• Naphthalenes (administration & dosage, chemical synthesis, pharmacology)
• Naphthols (administration & dosage, chemical synthesis, pharmacology)
• STAT3 Transcription Factor (metabolism)
• Xenograft Model Antitumor Assays