Flavones and flavonols may have clinical potential as CK2 inhibitors in cancer therapy

The serine-threonine kinase CK2, which targets over 300 cellular proteins, is overexpressed in all cancers,
presumably reflecting its ability to promote proliferation, spread, and survival through a wide range of complementary
mechanisms. Via an activating phosphorylation of Cdc373, a co-chaperone which partners with
Hsp90, CK2 prolongs the half-life of protein kinases that promote proliferation and survival in many cancers,
including Akt, Src, EGFR, Raf-1, and several cyclin-dependent kinases. CK2 works in other ways to boost the
activity of signaling pathways that promote cancer aggressiveness and chemoresistance, including those driven
by Akt, NF-kappaB, hypoxia-inducible factor-1, beta-catenin, TGF-beta, STAT3, hedgehog, Notch1, and the
androgen receptor; it promotes the epidermal-mesenchymal transition and aids efficiency of DNA repair. Several
potent and relatively specific inhibitors of CK2 are now being evaluated as potential cancer drugs; CX-4945 has
shown impressive activity in cell culture studies and xenograft models, and is now entering clinical trials.
Moreover, it has long been recognized that the natural flavone apigenin can inhibit CK2, with a Ki near 1 μM;
more recent work indicates that a range of flavones and flavonols, characterized by a planar structure and
hydroxylations at the 7 and 4′ positions – including apigenin, luteolin kaempferol, fisetin, quercetin, and
myricetin - can inhibit CK2 with Ki s in the sub-micromolar range. This finding is particularly intriguing in light
of the numerous studies demonstrating that each of these agents can inhibit the growth of cancer cells lines in
vitro and of human xenografts in nude mice. These studies attribute the cancer-retardant efficacy of flavones/
flavonols to impacts on a bewildering array of cellular targets, including those whose activities are boosted by
CK2; it is reasonable to suspect that, at least in physiologically achievable concentrations, these agents may be
achieving these effects primarily via CK2 inhibition. Inefficient absorption and rapid conjugation limit the
bioefficacy of orally administered flavonoids; however, the increased extracellular beta-glucuronidase of many
tumors may give tumors privileged access to glucuronidated flavonoids, and nanopartical technology can improve
the bioavailability of these agents. Enzymatically modified isoquercitrin has particular promise as a delivery
vehicle for quercetin. Hence, it may be worthwhile to explore the clinical potential of flavones/flavonols
as CK2 inhibitors for cancer therapy.