Effects of the CK2 inhibitors CX-4945 and CX-5011 on drug-resistant cells
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Updated: May 17, 2026
Identification of Novel CK2 Kinase Substrates Using a Versatile Biochemical Approach
Published on: February 21, 2019
Sofia Zanin1, Christian Borgo, Cristina Girardi
1Department of Biomedical Sciences and National Research Council Institute of Neurosciences, University of Padova, Padova, Italy.
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.
Insights
New protein kinase CK2 inhibitors, CX-4945 and CX-5011, effectively induce cancer cell death and overcome drug resistance. These compounds show promise in sensitizing resistant tumors to conventional chemotherapy, offering new therapeutic strategies.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Casein kinase 2 (CK2) is a key regulator of cell survival pathways with a global anti-apoptotic function.
- High CK2 expression in tumors makes it a promising therapeutic target for cancer treatment.
- Existing CK2 inhibitors like CX-4945 and CX-5011 are potent and selective but their efficacy against drug-resistant cancers is unknown.
Purpose of the Study:
- To evaluate the efficacy of CK2 inhibitors CX-4945 and CX-5011 in overcoming drug resistance in cancer.
- To investigate the potential of these inhibitors to re-sensitize resistant cancer cells to conventional chemotherapeutic agents.
Main Methods:
- Utilized drug-sensitive (S) and drug-resistant (R) variants of multiple tumor cell lines.
- Assessed the inhibition of endogenous CK2 activity by CX-4945 and CX-5011 in both S and R cells.
- Evaluated the induction of apoptosis and the combined effects of CK2 inhibitors with vinblastine or doxorubicin in resistant cells.
Main Results:
- CX-4945 and CX-5011 effectively inhibited CK2 activity (>50% reduction) in both sensitive and resistant cell lines at sub-micromolar concentrations.
- Both inhibitors induced apoptosis in both sensitive and resistant variants.
- Combined treatment with CX-4945 and vinblastine sensitized resistant cells to vinblastine.
- CX-4945 significantly increased doxorubicin accumulation in multidrug-resistant (MDR) cells, overcoming P-glycoprotein-mediated efflux.
Conclusions:
- CX-4945 and CX-5011 are effective in inducing apoptosis in drug-resistant cancer cells.
- These CK2 inhibitors can overcome multidrug resistance (MDR) phenomena, including P-glycoprotein-mediated drug efflux.
- The findings suggest that CK2 inhibitors hold significant potential for combination therapies to improve cancer treatment outcomes.
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