Inhibition of protein kinase CK2 by quercetin enhances CD95-mediated apoptosis in a human thymus-derived T cell line

•Quercetin is not cytotoxic per se, but sensitizes HPB-ALL cell line to apoptosis.•Protein kinase CK2 is overexpressed in leukemias and elevated levels of CK2 activity have been associated with an inferior prognosis.•Quercetin inhibits CK2 activity in an in vitro assay and in HPB-ALL cells.•CK2 inhibition by quercetin may contribute to sensitize HPB-ALL cells to CD95-induced apoptosis.

Quercetin (3,3′,4′,5,7-pentahydroxyflavone) is one of the major dietary flavonoid, found in a broad range of fruits, vegetables and beverages, such as tea and wine, with a daily uptake between 10 and 100 mg depending on the dietary attitude. We previously demonstrated that quercetin sensitizes HPB-ALL cell line to CD95-mediated apoptosis through a mechanism independent of its antioxidant properties and related to its ability to regulate the activity of serine-threonine protein kinases. Here, we report that quercetin is an inhibitor of protein kinase CK2, a kinase involved in apoptotic resistance in several forms of leukemia. Quercetin inhibits CK2 in an in vitro assay and in HPB-ALL cells decreasing its activity of 3.5-fold within 12 h from treatment, in good agreement with the intracellular concentration of the molecule measured by HPLC on the same cells (0.933 ± 0.188 μg/mg of total proteins). Quercetin also inhibits pure CK2 enzyme with an EC50 of about 150 nM in an in vitro assay. A specific CK2 inhibitor, TBB (4,5,6,7-tetra-bromo-benzo-triazole), behaves similarly to quercetin since it abolishes CK2 activity in HPB-ALL cells, but fails to enhance CD95-mediated apoptosis when associated with an anti-CD95 monoclonal antibody mimicking CD95 ligand. The resistance to apoptotic induction in HPB-ALL can be bypassed taking advantage of the pleiotropic activity of quercetin. Combined treatments which include quercetin in association with death receptor inducers may represent a novel therapeutic strategy against leukemia.