title: 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.affiliation: Department of Biomedical Sciences and National Research Council Institute of Neurosciences, University of Padova, Padova, Italy.
authors.forename: Sofia
authors.initials: S
authors.lastname: Zanin
authors.forename: Christian
authors.initials: C
authors.lastname: Borgo
authors.forename: Cristina
authors.initials: C
authors.lastname: Girardi
authors.forename: Sean E
authors.initials: SE
authors.lastname: O'Brien
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Miyata
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Pinna
authors.forename: Arianna
authors.initials: A
authors.lastname: Donella-Deana
authors.forename: Maria
authors.initials: M
authors.lastname: Ruzzene
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D006801:Humans; D009287:Naphthyridines / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D010619:Phenazines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D014747:Vinblastine / Q000494:pharmacology
chemical_list: C568365:5-(3-ethynylphenylamino)pyrimido(4,5-c)quinoline-8-carboxylic acid; D009287:Naphthyridines; D010619:Phenazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; D014747:Vinblastine; D004317:Doxorubicin; C555142:silmitasertib; D047390:Casein Kinase II