Effects of the CK2 inhibitors CX-4945 and CX-5011 on drug-resistant cells.

Abstract

CK2 is a pleiotropic protein kinase, which regulates many survival pathways and plays a global anti-apoptotic function. It is highly expressed in tumor cells, and is presently considered a promising therapeutic target. Among the many inhibitors available for this kinase, the recently developed CX-4945 and CX-5011 have proved to be very potent, selective and effective in inducing cell death in tumor cells; CX-4945 has recently entered clinical trials. However, no data are available on the efficacy of these compounds to overcome drug resistance, a major reasons of cancer therapy failure. Here we address this point, by studying their effects in several tumor cell lines, each available as variant R resistant to drug-induced apoptosis, and normal-sensitive variant S. We found that the inhibition of endogenous CK2 was very similar in S and R treated cells, with more than 50% CK2 activity reduction at sub-micromolar concentrations of CX-4945 and CX-5011. A consequent apoptotic response was induced both in S and R variants of each pairs. Moreover, the combined treatment of CX-4945 plus vinblastine was able to sensitize to vinblastine R cells that are otherwise almost insensitive to this conventional antitumor drug. Consistently, doxorubicin accumulation in multidrug resistant (MDR) cells was greatly increased by CX-4945.In summary, we demonstrated that all the R variants are sensitive to CX-4945 and CX-5011; since some of the treated R lines express the extrusion pump Pgp, often responsible of the MDR phenotype, we can also conclude that the two inhibitors can successfully overcome the MDR phenomenon.

• Authors: Sofia Zanin, Christian Borgo, Cristina Girardi, Sean E O'Brien, Yoshihiko Miyata, Lorenzo A Pinna, Arianna Donella-Deana, Maria Ruzzene
• Journal: PloS one (PLoS One) Vol. 7 Issue 11 Pg. e49193 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23145120 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-(3-ethynylphenylamino)pyrimido(4,5-c)quinoline-8-carboxylic acid
• Naphthyridines
• Phenazines
• Protein Kinase Inhibitors
• Pyrimidines
• Quinolines
• Vinblastine
• Doxorubicin
• silmitasertib
• Casein Kinase II

Topics

• Apoptosis (drug effects)
• Casein Kinase II (antagonists & inhibitors, metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Doxorubicin (pharmacology)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Drug Synergism
• Humans
• Naphthyridines (pharmacology)
• Neoplasms (drug therapy, genetics)
• Phenazines
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidines (pharmacology)
• Quinolines (pharmacology)
• Vinblastine (pharmacology)