3,6-Dihydroxyflavone

Molecules, 2014, 19(9):13200-13211.

Cytotoxic activity of 3,6-dihydroxyflavone in human cervical cancer cells and its therapeutic effect on c-Jun N-terminal kinase inhibition.[Pubmed: 25165860]

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.
METHODS AND RESULTS:
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.
CONCLUSIONS:
Therefore, 3,6-DHF may be a candidate inhibitor of JNKs, with potent anticancer effects.

Bulletin- Korean Chemical Society, 2011, 32329(9).

Antimicrobial Flavonoid, 3, 6-Dihydroxyflavone, Have Dual Inhibitory Activity against KAS III and KAS I.[Reference: WebLink]

Three types of β-ketoacyl acyl carrier protein synthase (KAS) are important for overcoming the bacterial resistance problem. Recently, we reported the discovery of a antimicrobial flavonoid, YKAF01 (3,6-Dihydroxyflavone), which exhibits antibacterial activity against Gram-positive bacteria through inhibition of β-ketoacyl acyl carrier protein synthase III (KAS III).
METHODS AND RESULTS:
In this report, we suggested that YKAF01 can be an inhibitor β-ketoacyl acyl carrier protein synthase I (KAS I) with dual inhibitory activity for KAS I as well as KAS III. KAS I is related to the elongation of unsaturated fatty acids in bacterial fatty acid synthesis and can be a good therapeutic target of designing novel antibiotics. We performed docking study of Escherichia coli KAS I (ecKAS I) and YKAF01, and determined their binding model. YKAF01 binds to KAS I with high binding affinity (2.12 × 10 6) and exhibited an antimicrobial activity against the multidrug-resistant E. coli with minimal inhibitory concentration (MIC) value of 512 μg/mL.
CONCLUSIONS:
Further optimization of this compound will be carried out to improve its antimicrobial activity and membrane permeability against bacterial cell membrane.

European Journal of Pharmacology, 2010, 648(1-3):31-38.

3,6-Dihydroxyflavone induces apoptosis in leukemia HL-60 cell via reactive oxygen species-mediated p38 MAPK/JNK pathway.[Pubmed: 20840847]

We have previously selected a promising anti-cancer agent 3,6-Dihydroxyflavone by pharmacodynamic experiments.
METHODS AND RESULTS:
In the present study, we investigated its pro-apoptosis mechanisms in leukemia HL-60 cell. Our data revealed that 3,6-Dihydroxyflavone dose- and time-dependently decreases cell viability and induces apoptosis by activating caspase cascade, cleaving poly (ADP-ribose) polymerase (PARP). The anti-cancer effects of 3,6-Dihydroxyflavone are associated with the generation of reactive oxygen species, the altered glutathione-redox balance as significantly decreased glutathione (GSH) and its ratio to gluthatione disulfide (GSSG), and the accumulation of lipid peroxidation indicator malondialdehyde. Addition of antioxidant N-acetylcysteine (NAC) prevents the elevation of reactive oxygen species induced by 3,6-Dihydroxyflavone and partially suppresses the cytotoxic effects. Furthermore, 3,6-Dihydroxyflavone reduces cell membrane fluidity and induces the loss of mitochondrial membrane potential. 3,6-Dihydroxyflavone was also found to modulate the activities of mitogen-activated protein kinase (MAPK) family members, which includes increased protein kinase of 38 kDa (p38), c-Jun N-terminal kinase (JNK), and decreased extracellular signal-regulated kinase (ERK) activation. The effect of 3,6-Dihydroxyflavone on MAPKs pathway could be abrogated by co-treatment with NAC.
CONCLUSIONS:
Taking together, our data suggested that 3,6-Dihydroxyflavone increases intracellular oxidative stress and lipid peroxidation, thereby affecting the physical and functional properties of plasma membrane, as well as MAPKs signal pathway, which are likely to play a role in the 3,6-Dihydroxyflavone-induced HL-60 cell cytotoxicities.