Cytotoxic Activity of 3,6-Dihydroxyflavone in Human Cervical Cancer Cells and Its Therapeutic Effect on c-Jun N-Terminal Kinase Inhibition
| Autor: | Yong-Seok Heo, Ki-Woong Jeong, Areum Shin, Yangmee Kim, Hum Nath Jnawali, Eun-Jung Lee |
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| Rok vydání: | 2014 |
| Předmět: |
MAPK/ERK pathway
kinase p38 mitogen-activated protein kinases Uterine Cervical Neoplasms Pharmaceutical Science anticancer effect 3 6-dihydroxyflavone western blotting binding model Article Analytical Chemistry lcsh:QD241-441 HeLa lcsh:Organic chemistry Drug Discovery Humans Cytotoxic T cell Phosphorylation Physical and Theoretical Chemistry Protein kinase A Receptor Flavonoids biology Chemistry Kinase Organic Chemistry c-jun JNK Mitogen-Activated Protein Kinases virus diseases Hydrogen Bonding biology.organism_classification Molecular biology Neoplasm Proteins Gene Expression Regulation Neoplastic Chemistry (miscellaneous) Molecular Medicine Female |
| Zdroj: | Molecules, Vol 19, Iss 9, Pp 13200-13211 (2014) Molecules Molecules; Volume 19; Issue 9; Pages: 13200-13211 |
| ISSN: | 1420-3049 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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