casein-kinase-ii and myricetin

The role of Wnt signalling in carcinogenesis suggests compounds targeting this pathway as potential anti-cancer drugs. Several studies report activation of Wnt signalling in biliary tract cancer (BTC) thus rendering Wnt inhibitory drugs as potential candidates for targeted therapy of this highly chemoresistant disease.. In this study we analysed five compounds with suggested inhibitory effects on Wnt signalling (DMAT, FH535, myricetin, quercetin, and TBB) for their cytotoxic efficiency, mode of cell death, time- and cell line-dependent characteristics as well as their effects on Wnt pathway activity in nine different BTC cell lines.. Exposure of cancer cells to different concentrations of the compounds results in a clear dose-dependent reduction of viability for all drugs in the order FH535 > DMAT > TBB > myricetin > quercetin. The first three substances show high cytotoxicity in all tested cell lines, cause a direct cytotoxic effect by induction of apoptosis and inhibit pathway-specific signal transduction in a Wnt transcription factor reporter activity assay. Selected target genes such as growth-promoting cyclin D1 and the cell cycle progression inhibitor p27 are down- and up-regulated after treatment, respectively.. Taken together, these data demonstrate that the small molecular weight inhibitors DMAT, F535 and TBB have a considerable cytotoxic and possibly Wnt-specific effect on BTC cell lines in vitro. Further in vivo investigation of these drugs as well as of new Wnt inhibitors may provide a promising approach for targeted therapy of this difficult-to-treat tumour.

Topics: Antineoplastic Agents; Benzimidazoles; beta Catenin; Biliary Tract Neoplasms; Cadherins; Cell Line, Tumor; Cell Survival; Clinical Trials as Topic; Cyclin D1; Flavonoids; Gene Expression Regulation, Neoplastic; Genes, p53; Humans; Ki-67 Antigen; Proliferating Cell Nuclear Antigen; Quercetin; RNA, Messenger; Sulfonamides; Triazoles; Vimentin; Wnt Signaling Pathway

To observe the effect of 7 flavonoids on recombinant human protein kinase CK 2 holoenzyme activity and investigate their structure-activity relationship.. Recombinant human protein kinase CK 2 alpha' and beta subunits were mixed at equal molar ratio to reconstitute CK 2 holoenzyme. The CK 2 activity was assayed by detecting incorporation of (32)P of [gamma-(32)P]ATP into the substrate for the inhibitory effect by flavonoids and calculation of IC50 was performed according to probability unit (PROBIT) method.. Myricetin, quercetin, morin, luteolin, kaempferol, apigenin, and chrysin were shown to obviously inhibit recombinant CK 2 holoenzyme activity in a concentration-dependent manner with IC50 values of 1.18, 0.51, 16.16, 0.86, 1.88, 1.72, and 13.63 micromol/L, respectively. Myricetin, quercetin, luteolin, kaempferol, and apigenin were more effective than DRB and A3, which were known as CK 2 inhibitors in vitro. Whereas morin and chrysin displayed a similar effect to DRB. Structure-activity study indicated that the major structural requirements for the potent inhibition of CK 2 by these flavonoids were hydroxyl group at position 6, 3' and 4'. Different from these requirements, absence of a hydroxyl group at position 3 did not modify their inhibitory potency, while addition of hydroxyl groups at positions 2' or 5' was detrimental to the inhibitory effect on CK 2.. The inhibitory effect of flavonoid on protein kinase CK 2 in vitro may be determined by the position of their hydroxyl groups.

Topics: Casein Kinase II; Flavonoids; Holoenzymes; Humans; Hydroxyl Radical; Luteolin; Quercetin; Recombinant Proteins; Structure-Activity Relationship