Cytotoxic activity of 3,6-dihydroxyflavone in human cervical cancer cells and its therapeutic effect on c-jun n-terminal kinase inhibition
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Authors
Lee, Eunjung
Jeong, Ki-Woong
Jnawali, Hum Nath
Shin, Areum
Heo, Yong-Seok
Kim, Yangmee
Issue Date
2014-08-27
Type
Article
Language
en_US
Keywords
Anticancer Effect , 3,6-Dihydroxyflavone , Western Blotting , Binding Model , Kinase
Alternative Title
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.
Description
Citation
Lee, E., Jeong, K. W., Jnawali, H. N., Shin, A., Heo, Y. S., & Kim, Y. (2014). Cytotoxic activity of 3,6-dihydroxyflavone in human cervical cancer cells and its therapeutic effect on c-Jun N-terminal kinase inhibition. Molecules (Basel, Switzerland), 19(9), 13200–13211. https://doi.org/10.3390/molecules190913200
Publisher
Molecules (Basel, Switzerland)