title: Cytotoxic activity of 3,6-dihydroxyflavone in human cervical cancer cells and its therapeutic effect on c-Jun N-terminal kinase inhibition.
abstract: Previously we have shown that 3,6-dihydroxyflavone (3,6-DHF) is a potent agonist of the human peroxisome proliferator-activated receptor (hPPAR) with cytotoxic effects on human cervical cancer cells. To date, the mechanisms by which 3,6-DHF exerts its antitumor effects on cervical cells have not been clearly defined. Here, we demonstrated that 3,6-DHF exhibits a novel antitumor activity against HeLa cells with IC50 values of 25 μM and 9.8 μM after 24 h and 48 h, respectively. We also showed that the anticancer effects of 3,6-DHF are mediated via the toll-like receptor (TLR) 4/CD14, p38 mitogen-activated protein kinase (MAPK), Jun-N terminal kinase (JNK), extracellular-signaling regulated kinase (ERK), and cyclooxygenase (COX)-2 pathways in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. We found that 3,6-DHF showed a similar IC50 (113 nM) value to that of the JNK inhibitor, SP600125 (IC50 = 118 nM) in a JNK1 kinase assay. Binding studies revealed that 3,6-DHF had a strong binding affinity to JNK1 (1.996 × 105 M-1) and that the 6-OH and the carbonyl oxygen of the C ring of 3,6-DHF participated in hydrogen bonding interactions with the carbonyl oxygen and the amide proton of Met111, respectively. Therefore, 3,6-DHF may be a candidate inhibitor of JNKs, with potent anticancer effects.
authors.affiliation: Department of Bioscience and Biotechnology, Bio-Molecular Informatics Center, Institute of KU Biotechnology, Konkuk University, Seoul 143-701, Korea. eun0808@konkuk.ac.kr.
authors.forename: Eunjung
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Bioscience and Biotechnology, Bio-Molecular Informatics Center, Institute of KU Biotechnology, Konkuk University, Seoul 143-701, Korea. znznzn00@konkuk.ac.kr.
authors.forename: Ki-Woong
authors.initials: KW
authors.lastname: Jeong
authors.affiliation: Department of Bioscience and Biotechnology, Bio-Molecular Informatics Center, Institute of KU Biotechnology, Konkuk University, Seoul 143-701, Korea. humnath@konkuk.ac.kr.
authors.forename: Hum Nath
authors.initials: HN
authors.lastname: Jnawali
authors.affiliation: Department of Bioscience and Biotechnology, Bio-Molecular Informatics Center, Institute of KU Biotechnology, Konkuk University, Seoul 143-701, Korea. byeol@konkuk.ac.kr.
authors.forename: Areum
authors.initials: A
authors.lastname: Shin
authors.affiliation: Department of Chemistry of Konkuk University, Seoul 143-701, Korea. ysheo@konkuk.ac.kr.
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Heo
authors.affiliation: Department of Bioscience and Biotechnology, Bio-Molecular Informatics Center, Institute of KU Biotechnology, Konkuk University, Seoul 143-701, Korea. ymkim@konkuk.ac.kr.
authors.forename: Yangmee
authors.initials: Y
authors.lastname: Kim
mesh_terms: D005260:Female; D005419:Flavonoids / Q000008:administration & dosage*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006860:Hydrogen Bonding / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D010766:Phosphorylation / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: C555160:3,6-dihydroxyflavone; D005419:Flavonoids; D009363:Neoplasm Proteins; D048031:JNK Mitogen-Activated Protein Kinases