Execution of the mitochondrial death signaling is paramount to an effective response of cancer cells to chemotherapeutic intervention. Therefore, factors that inhibit the engagement of the mitochondrial amplification pathway, such as the expression of the anti-apoptotic proteins of the Bcl2 family or inactivation of inducers of mitochondrial permeability, play a critical role in the acquisition of the resistant phenotype. Protein kinase CK2 (CK2) is a ubiquitous serine/threonine kinase that is highly conserved in eukaryotic cells. This multifunctional protein kinase has been shown to impact cell growth and proliferation, as numerous growth-related proteins are substrates of CK2. More importantly, experimental evidence linking increased expression and activity of the kinase to human cancers, underscores the relevance of CK2 biology to cellular transformation and carcinogenesis. Of note, among the many cellular substrates of CK2 are proteins involved in the efficient execution of the mitochondria-dependent cell death signaling, such as Bid, caspase-2, ARC and others. Supporting this, recent reports have demonstrated that genetic manipulation of CK2 expression as well as pharmacological inhibition of its enzymatic activity sensitizes cancer cells to apoptotic stimuli. Due to the critical regulatory role that this kinase plays in cell fate determination in cancer cells, there is a tremendous increase in activity geared at the development of CK2-specific therapies. Here we provide a brief review of CK2-mediated inhibition of mitochondrial death signaling in cancer cells and its implications for the design of novel target specific therapeutic strategies.
"These effects were evaluated in the presence of 10 μM ATP. The three compounds were coumestrol (1-F4; 3,9-Dihydroxy-6-benzofurano [3,2-c]chromenone), curcumin (1-D6; (1E,6E)-1,7-Bis(4-hydroxy-3-methoxy phenyl)-1,6-heptadiene-3,5-dione) and aristolochic acid I (1-F3; 8-methoxy-6-nitro phenanthro[3,4-d] [1,3] dioxole-5-carboxylic acid (Figure 1B). Although all curcumin and aristolochic acid 1 showed more than 50% inhibition of kinase activity at 10 μM, coumestrol completely inhibited CK2. "
[Show abstract][Hide abstract] ABSTRACT: Casein kinase 2 (CK2) is involved in various cellular events such as proliferation, apoptosis, and the cell cycle. CK2 overexpression is associated with multiple human cancers and may therefore be a promising target for cancer therapy. To identity novel classes of inhibitors for CK2, we screened a natural product library obtained from National Cancer Institute.
The quantitative luminescent kinase assay ADP-GloTM was used to screen CK2 inhibitors from the natural product library. The same assay was used to determine cell-free dose-dependent response of CK2 inhibitors and conduct a kinetic study. Docking was performed to predict the binding patterns of selected CK2 inhibitors. Western blot analysis was used to evaluate Akt phosphorylation specific to CK2 and apoptosis effect. The cell viability assay CellTiter-Glo(R) was used to evaluate the inhibition effects of CK2 inhibitors on cancer cells.
We identified coumestrol as a novel reversible ATP competitive CK2 inhibitor with an IC50 value of 228 nM. Coumestrol is a plant-derived compound that belongs to the class of phytoestrogens, natural compounds that mimic the biological activity of estrogens. In our study, coumestrol showed high selectivity among 13 kinases. The hydrogen bonds formed between coumestrol and the amino acids in the ATP binding site were first reviewed by a molecular docking study that suggested a possible interaction of coumestrol with the hinge region of ATP site of CK2. In addition, coumestrol inhibited cancer cell growth partially through down-regulation of CK2-specific Akt phosphorylation. Finally, coumestrol exerted strong inhibition effects on the growth of three cancer cell lines.
Our study shows that coumestrol, a novel ATP competitive and cell permeable CK2 inhibitor with submicromolar IC50, had inhibition effects on the growth of three cancer cell lines and may represent a promising class of CK2 inhibitors.
[Show abstract][Hide abstract] ABSTRACT: In a set of B10-loaded C-2 emulsions exposed to eight neutron energies in the range 6-20 Mev, 1541 three-prong stars were found which were caused by either the B10(n, t2α) or the B10(n, dn′2α) reaction. The triton cross section at 14 Mev is 102±17 mb and decreases with increasing bombarding energy, while the deuteron cross section is 128±19 mb and increases slightly with energy. The triton reaction proceeds partially through the 4.61-Mev state in Li7 and partially as a three-body breakup. In the deuteron reaction the following intermediate nuclei are formed: Be9, 2.43-Mev state; Be8, ground state and possibly the 2.9-Mev level; Li7, 10.8- and 12.4-Mev levels; and Li6, 2.19-Mev level. Four examples were found of the N14(n, t3α) reaction. The feasibility of using the B10(n, t2α) reaction as a neutron monitor is discussed.
Alexandra S. Dubrovina, Konstantin V. Kiselev, Valeriya S. Khristenko, Olga A. Aleynova
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