Flavones and Flavonols may have Clinical Potential as CK2 Inhibitors in Cancer

Abstract

The serine-threonine kinase CK2, which targets over 300 cellular proteins, is over
expressed 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, STAT3, hedgehog,
Notch1, and the androgen receptor; it also 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 micromolar;
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, keampferol,
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.