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.