Efficacy and mechanism of anti-tumor action of new potential CK2 inhibitors toward glioblastoma cells

Kaminska,

doi:10.3892/ijo_00000424

Cited by 30 publications

(33 citation statements)

References 41 publications

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“…This difference suggests that they inhibit both nNOS and eNOS at this concentration, and raises the possibility that specific inhibition of one of these isoforms might be possible at a lower concentration. The latter possibility may be of importance for possible future in vivo studies, because compound 1o at 10 µM shows substantial toxicity in primary cultures of normal rat cortical astrocytes (Kaminska et al, 2009). …”

Section: Resultsmentioning

confidence: 98%

“…However, a rapidly growing body of evidence demonstrates multiple potentially beneficial biological activities of its derivatives. Some of these compounds show potential as prodrugs of the alcohol deterrent agent cyanamide (Shirota et al, 1997), inhibitors of HIV capsid assembly (Li et al, 2009b), blockers of the CXCR4 chemokine receptors with potential for preventing HIV infection of target cells (Thoma et al, 2008), anticancer drugs (for review see Li et al, 2009a), hypoglycaemic drugs (Zhang et al, 2009), calcium blockers with potential neuroprotectant and cognition enhancer capability (Perlovich et al, 2009), anti-HCV agents with high selectivity index (Kang et al, 2009), and proapoptotic agents with substantial toxicity toward human glioblastoma cells in vitro (Kaminska et al, 2009). However, most attention is being given to these drugs as nitric oxide synthase (NOS) inhibitors with variable NOS isoform selectivity (Szabo et al, 1994;Southan et al, 1995;Handy et al, 1996;Wang et al, 1998;Paquay et al, 1999;Ijuin et al, 2005;Jin et al, 2009) and antimicrobial agents.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and antimicrobial and nitric oxide synthase inhibitory activities of novel isothiourea derivatives

et al. 2010

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The reaction of substituted benzylhalides, or of halomethyl derivatives of thiophene or furane, with thiourea or its derivatives yielded the respective isothioureas as hydrohalide salts. The products (a total of 17, including 16 novel compounds) were tested for activity against five Gram-positive and nine Gram-negative bacterial strains, six yeast species and two protozoan species. The most active against Gram-positive bacteria were S-(2,4-dinitrobenzyl)isothiourea hydrochloride (MIC range for four out of five strains tested: 12.5-25 microg/mL) and S-(2,3,4,5,6-pentabromobenzyl)isothiourea hydrobromide (MIC range: 12.5-50 microg/mL). The lowest MICs of novel isothioureas for yeast and Gram-negative bacteria ranged between 50 and 100 microg/mL. Nine novel isothioureas showed appreciable genotoxicity in the Bacillus subtilis 'rec-assay' test, the most potent being S-2-(5-nitrofuran-2-ylmethyl)isothiourea and S-(2-nitrobenzyl) isothiourea. At 10 muM concentration, S-(3,4-dichlorobenzyl)isothiourea hydrochloride and S-(2,3,4,5,6-pentabromobenzyl)isothiourea hydrobromide inhibited Ca(2+)/calmodulin-dependent (non-inducible) nitric oxide synthase activity in normal rat brain homogenates stronger (p < 0.05) than the reference drug 7-nitroindazole (by 78, 76 and 60%, respectively); ten other new isothiourea derivatives significantly inhibited the activity to a lower extent (by 28-60%). These results extend the list of promising isothioureas with substantial activity in vitro and suggest that an in-depth study of toxicity, antimicrobial properties in vivo and nitric oxide synthase isoform selectivity of selected novel compounds is warranted.

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Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Synthesis and antimicrobial and nitric oxide synthase inhibitory activities of novel isothiourea derivatives

et al. 2010

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“…Non-specific CK2 inhibitors such as TBB and DMAT exhibit cytotoxic potential towards GBM cells in vitro (22), Ellipticine and benzopyridoindole derivatives, which inhibit CK2 activity, display antitumor activity in a flank model of GBM (23), and azonaphthalene derivatives, allosteric inhibitors of CK2, inhibit growth of U373-MG cells in the flank (24). Downregulation of CK2 by siRNA induces death of the GBM cell line M059K (25).…”

Section: Introductionmentioning

confidence: 99%

Targeting Protein Kinase CK2 Suppresses Prosurvival Signaling Pathways and Growth of Glioblastoma

Zheng

McFarland

Drygin

et al. 2013

Clinical Cancer Research

124

138

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Purpose Gliomas are the most frequently occurring primary malignancies in the brain, and glioblastoma (GBM) is the most aggressive of these tumors. Protein kinase CK2 is composed of two catalytic subunits (α and/or α’) and two β regulatory subunits. CK2 suppresses apoptosis, promotes neo-angiogenesis, and enhances activation of the JAK/STAT, NF-κB, PI3K/AKT, Hsp90, Wnt and Hedgehog pathways. Aberrant activation of the NF-κB, PI3K/AKT and JAK/STAT-3 pathways is implicated in GBM progression. Since CK2 is involved in their activation, the expression and function of CK2 in GBM was evaluated. Experimental Design and Results Analysis of 537 GBMs from The Cancer Genome Atlas Project demonstrates the CSNK2A1 gene, encoding CK2α, has gene dosage gains in GBM (33.7%), and is significantly associated with the classical GBM subtype. Inhibition of CK2 activity by CX-4945, a selective CK2 inhibitor, or CK2 knockdown by siRNA suppresses activation of the JAK/STAT, NF-κB and AKT pathways and downstream gene expression in human GBM xenografts. On a functional level, CX-4945 treatment decreases the adhesion and migration of GBM cells, in part through inhibition of integrin β1 and α4 expression. In vivo, CX-4945 inhibits activation of STAT-3, NF-κB p65 and AKT, and promotes survival of mice with intracranial human GBM xenografts. Conclusions CK2 inhibitors may be considered for treatment of patients with GBM.

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“…The advent of highly specific pharmacological inhibitors of CK2 has also been driven by the fact that these compounds exhibit antigrowth and anticancer activities [44, 45], reflecting an important role of CK2 in cell growth. The fact that CSQ2 is the major substrate for CK2 in heart homogenates is consistent with a possible role of CSQ2 phosphorylation in cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

The cytosolic protein kinase CK2 phosphorylates cardiac calsequestrin in intact cells

et al. 2011

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The luminal SR protein CSQ2 contains phosphate on roughly half of the serines found in its C-terminus. The sequence around phosphorylation sites in CSQ2 suggest that the in vivo kinase is protein kinase CK2, even though this enzyme is thought to be present only in the cytoplasm and nucleus. To test whether CSQ2 kinase is CK2, we combined approaches that reduced CK2 activity and CSQ2 phosphorylation in intact cells. Tetrabromocinnamic acid, a specific inhibitor of CK2, inhibited both the CSQ2 kinase and CK2 in parallel across a range of concentrations. In intact primary adult rat cardiomyocytes and COS cells, 24 h of drug treatment reduced phosphorylation of overexpressed CSQ2 by 75%. Down-regulation of CK2α subunits in COS cells using siRNA, produced a 90% decrease in CK2α protein levels, and CK2-silenced COS cells exhibited a twofold reduction in CSQ2 kinase activity. Phosphorylation of CSQ2 overexpressed in CK2-silenced cells was also reduced by a factor of two. These data suggested that CSQ2 in intact cells is phosphorylated by CK2, a cytosolic kinase. When phosphorylation site mutants were analyzed in COS cells, the characteristic rough endoplasmic reticulum form of the CSQ2 glycan (GlcNAc2Man9,8) underwent phosphorylation site dependent processing such that CSQ2-nonPP (Ser to Ala mutant) and CSQ2-mimPP (Ser to Glu mutant) produced apparent lower and greater levels of ER retention, respectively. Taken together, these data suggest CK2 can phosphorylate CSQ2 co-translationally at biosynthetic sites in rough ER, a process that may result in changes in its subsequent trafficking through the secretory pathway.

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Efficacy and mechanism of anti-tumor action of new potential CK2 inhibitors toward glioblastoma cells

Cited by 30 publications

References 41 publications

Synthesis and antimicrobial and nitric oxide synthase inhibitory activities of novel isothiourea derivatives

Synthesis and antimicrobial and nitric oxide synthase inhibitory activities of novel isothiourea derivatives

Targeting Protein Kinase CK2 Suppresses Prosurvival Signaling Pathways and Growth of Glioblastoma

The cytosolic protein kinase CK2 phosphorylates cardiac calsequestrin in intact cells

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