| Summary: | CK2 is a serine/threonine kinase, with 2 catalytic subunits (α and α’) and 2 regulatory subunits (β). CK2 phosphorylates and activates substrates in several pathways implicated in cancer progression such as PI3K/AKT, NF-κB, and JAK/STAT pathways; thus increased CK2 activity can promote cancer growth. Abnormally high levels of CK2 expression at the DNA, RNA, and protein levels have been found in many studies of several different cancer types. Inhibition of CK2 using antisense oligonucleotides (ASOs) designed to target various CK2 subunits and thus inhibit phosphorylation of CK2 substrates decreases signaling through the various pathways implicated in cancer progression. As such, treatment with CK2 ASOs leads to decreased cancer cell proliferation, cell-cycle arrest, as well as decreased cell viability. CK2 inhibition using specific inhibitors such as TBB, CIGB-300, CX-4945, quinalizarin, emodin has achieved similar efficacy in inhibiting CK2, displaying reduction of cell viability, decreased cell proliferation, induction of apoptosis, and inhibition of PI3K/AKT, NF-kB, and JAK/STAT signaling pathways in several cancer cell models. Inhibition of the PI3K/AKT and NF-kB pathways was demonstrated by presence of decreased phosphorylated active forms of CK2 substrates, as well as reduced amounts of other phosphorylated substrates downstream. Use of these CK2 inhibitors in vivo has also shown promising results, as mice inoculated with solid tumors from a wide range of cancer types have responded promisingly to treatment with CK2 inhibitors. Mice treated with CK2 inhibitors in these studies show improved survival, decreased cell proliferation, and reduced tumor volume in comparison to vehicle-treated control mice. In addition, these mice have lower quantities of phosphorylated CK2 substrates, including those in the PI3K/AKT, and NF-kB cascades. Further, CK2 inhibition has proven to be efficacious when used in combination with other chemotherapeutics, with combination treatment often showing greater efficacy when compared to either monotherapy (CK2 inhibition alone or chemotherapy alone) in both cell models and in xenograft mice. In cells models, these combination therapies have shown significantly greater reduction in cell viability and proliferation, and induced apoptosis to a greater extent that either CK2 inhibition or chemotherapy administered alone, with these trends observed in cell lines that are typically resistant to the chemotherapeutic being used (e.g. cisplatin, or paclitaxel). Similarly, xenograft mice treated with combination dosing regimens of CK2 inhibitor and a traditional chemotherapeutic have also shown greater anti-cancer effects when compared to mice treated with either therapy alone; combination treatment mice often have decreased tumor volume, less tumor growth, and a significant increase in survival, as well as apparent inhibition of CK2-dependent phosphorylation cascades. CK2 inhibitors CX-4945 and CIGB-300 have also been used in human patient clinical trials, with CIGB-300 showing tolerability and efficacy when used for treatment of invasive cervical cancer via intralesional injection.
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