Coumestrol from the national cancer Institute’s natural product library is a novel inhibitor of protein kinase CK2

Abstract

BackgroundCasein 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.MethodsThe quantitative luminescent kinase assay ADP-Glo™ 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® was used to evaluate the inhibition effects of CK2 inhibitors on cancer cells.ResultsWe 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.ConclusionOur 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.

Beneficial Effects of Pterocarpan-High Soybean Leaf Extract on Metabolic Syndrome in Overweight and Obese Korean Subjects: Randomized Controlled Trial

“…A kaempferol glycoside (KG)-rich fraction from unripe soybean leaf attenuated blood glucose and hepatic lipid levels in KK-A y mice [19]. In particular, pterocarpans such as coumesterol, glyceofuran, glyceollin III suppressed the oxidation of low-density lipoprotein (LDL) [20], and have been reported to have cancer prevention and anti-inflammatory effects [21,22,23]. In addition, glyceollins (I–III), prenylated pterocarpan have known antiestrogenic effects in vivo [24,25].…”

Antiherpes evaluation of soybean isoflavonoids

“…The biological properties of coumestrol, another isoflavonoid found in soybeans, have also been investigated [10][11][12]. This molecule is a soy isoflavone-like compound with a coumestan skeleton that has a more potent estrogen receptor affinity than other soy isoflavonoids [13].…”

Coumestrol suppresses proliferation of ES2 human epithelial ovarian cancer cells

“…It has potential therapeutic activities against carcinogenesis, neurological disorders, and autoimmune diseases through action as an antagonist to estrogen or other estrogenic chemicals for binding to ESR1/ESR2 (Schoenroth et al 2004, Musgrove & Sutherland 2009, de Leeuw et al 2011. Coumestrol acts as a novel inhibitor of protein kinase CK2 which is a abundantly expressed in human cancers including epithelial ovarian cancer (EOC) and is closely linked to cell proliferation, inhibition of apoptosis and oncogenesis in various cancer cell lines from the cervix, lung and prostate, as well as leukemic cells (Ahmad et al 2008, Duncan & Litchfield 2008, Liu et al 2013, Cho et al 2014. In addition, coumestrol induces cellular senescence by stimulating production of ROS through p53-p21…”