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Pharmaceuticals (Basel). 2017 Feb 12;10(1). pii: E24. doi: 10.3390/ph10010024.

Targeting Protein Kinase CK2: Evaluating CX-4945 Potential for GL261 Glioblastoma Therapy in Immunocompetent Mice.

Author information

1
Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Biociències, Edifici C, Universitat Autònoma de Barcelona, Cerdanyola del Vallès 08193, Spain. Laura.Ferrer@uab.cat.
2
Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Cerdanyola del Vallès 08193, Spain. Laura.Ferrer@uab.cat.
3
Institut de Biotecnologia i de Biomedicina (IBB), Universitat Autònoma de Barcelona, Cerdanyola del Vallès 08193, Spain. Laura.Ferrer@uab.cat.
4
Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Biociències, Edifici C, Universitat Autònoma de Barcelona, Cerdanyola del Vallès 08193, Spain. Lucia.Villamanan@uab.cat.
5
Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Biociències, Edifici C, Universitat Autònoma de Barcelona, Cerdanyola del Vallès 08193, Spain.
6
Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Cerdanyola del Vallès 08193, Spain.
7
Department of Biomedical Sciences, University of Padova, Padova 35131, Italy. jordivilardellvila@gmail.com.
8
Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Biociències, Edifici C, Universitat Autònoma de Barcelona, Cerdanyola del Vallès 08193, Spain. Maria.Plana@uab.cat.
9
Department of Biomedical Sciences, University of Padova, Padova 35131, Italy. maria.ruzzene@unipd.it.
10
Department of Biomedical Sciences, University of Padova, Padova 35131, Italy. lorenzo.pinna@unipd.it.
11
Consiglio Nazionale delle Ricerche (CNR), Neuroscience Institute, Padova 35131, Italy. lorenzo.pinna@unipd.it.
12
Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Biociències, Edifici C, Universitat Autònoma de Barcelona, Cerdanyola del Vallès 08193, Spain. Emili.Itarte@uab.cat.
13
Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Biociències, Edifici C, Universitat Autònoma de Barcelona, Cerdanyola del Vallès 08193, Spain. Carles.Arus@uab.es.
14
Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Cerdanyola del Vallès 08193, Spain. Carles.Arus@uab.es.
15
Institut de Biotecnologia i de Biomedicina (IBB), Universitat Autònoma de Barcelona, Cerdanyola del Vallès 08193, Spain. Carles.Arus@uab.es.
16
Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Cerdanyola del Vallès 08193, Spain. AnaPaula.Candiota@uab.cat.
17
Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Biociències, Edifici C, Universitat Autònoma de Barcelona, Cerdanyola del Vallès 08193, Spain. AnaPaula.Candiota@uab.cat.
18
Institut de Biotecnologia i de Biomedicina (IBB), Universitat Autònoma de Barcelona, Cerdanyola del Vallès 08193, Spain. AnaPaula.Candiota@uab.cat.

Abstract

Glioblastoma (GBM) causes poor survival in patients even with aggressive treatment. Temozolomide (TMZ) is the standard chemotherapeutic choice for GBM treatment but resistance always ensues. Protein kinase CK2 (CK2) contributes to tumour development and proliferation in cancer, and it is overexpressed in human GBM. Accordingly, targeting CK2 in GBM may benefit patients. Our goal has been to evaluate whether CK2 inhibitors (iCK2s) could increase survival in an immunocompetent preclinical GBM model. Cultured GL261 cells were treated with different iCK2s including CX-4945, and target effects evaluated in vitro. CX-4945 was found to decrease CK2 activity and Akt(S129) phosphorylation in GL261 cells. Longitudinal in vivo studies with CX-4945 alone or in combination with TMZ were performed in tumour-bearing mice. Increase in survival (p < 0.05) was found with combined CX-4945 and TMZ metronomic treatment (54.7 ± 11.9 days, n = 6) when compared to individual metronomic treatments (CX-4945: 24.5 ± 2.0 and TMZ: 38.7 ± 2.7, n = 6) and controls (22.5 ± 1.2, n = 6). Despite this, CX-4945 did not improve mice outcome when administered on every/alternate days, either alone or in combination with 3-cycle TMZ. The highest survival rate was obtained with the metronomic combined TMZ+CX-4945 every 6 days, pointing to the participation of the immune system or other ancillary mechanism in therapy response.

KEYWORDS:

CK2 inhibitors; CX-4945; GBM therapeutic target; Glioma; immune system; metronomic therapy; preclinical brain tumour

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