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Molecules 2014, 19(9), 13200-13211; doi:10.3390/molecules190913200

Cytotoxic Activity of 3,6-Dihydroxyflavone in Human Cervical Cancer Cells and Its Therapeutic Effect on c-Jun N-Terminal Kinase Inhibition

Department of Bioscience and Biotechnology, Bio-Molecular Informatics Center, Institute of KU Biotechnology, Konkuk University, Seoul 143-701, Korea
Department of Chemistry of Konkuk University, Seoul 143-701, Korea
Author to whom correspondence should be addressed.
Received: 15 July 2014 / Revised: 18 August 2014 / Accepted: 22 August 2014 / Published: 27 August 2014
(This article belongs to the Special Issue Design and Study of Kinase Inhibitors)
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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 M1) 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. View Full-Text
Keywords: anticancer effect; 3,6-dihydroxyflavone; western blotting; binding model; kinase anticancer effect; 3,6-dihydroxyflavone; western blotting; binding model; kinase

This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Lee, E.; Jeong, K.-W.; Jnawali, H.N.; Shin, A.; Heo, Y.-S.; Kim, Y. Cytotoxic Activity of 3,6-Dihydroxyflavone in Human Cervical Cancer Cells and Its Therapeutic Effect on c-Jun N-Terminal Kinase Inhibition. Molecules 2014, 19, 13200-13211.

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