Human protein kinase CK2 is a ubiquitous serine/threonine kinase involved in many cellular functions, including cell viability, cell proliferation, and malignant transformation. Constitutive activity of CK2, levels of which are frequently elevated in tumours, may contribute to enhanced cell proliferation and resistance to apoptosis. Gliomas are the most common and dangerous brain tumours. Due to lack of effective treatments most patients diagnosed with malignant gliomas survive <1 year.

We compared effects of widely applied CK2 inhibitors: 4,5,6,7-tetrabromobenzotriazole (TBBt), the structurally related 4,5,6,7- tetrabromobenzimidazole (TBBi) and  2-dimethylamino-4,5,6,7-tetrabromobenzimidazole (DMAT) with an efficiency of recently developed derivatives of TBBt, TBBi and pentabromobenzyl-isothioureas on cultured rat glioma cells.

The new derivatives N-hydroxypropyl substituted TBBt (N1-PrOH-TBBt and N2-PrOH-TBBt) and N1-PrOH-TBBi were obtained by the alkylation of TBBt or TBBi with 3-bromopropan-1-ol and DBU in acetonitrile. The derivatives of pentabromobenzyl-isothiourea (ZKK-1): N-Methyl- (ZKK-2), N,N-dimethyl- (ZKK-3), N-ethyl- (ZKK-4), N-allyl (ZKK-5), N-phenyl (ZKK-6), were obtained in the reaction of pentabromobenzylbromide with N-substituted thioureas.

New derivatives (ZKK 1-6) and N1-hydroxypropyl derivatives of TBBi and TBBt were more effective than TBBt in inducing growth arrest and cell death in glioma cells when tested at 0.05mM during 48h. TBBi and ZKK-1 strongly induced apoptotic death involving caspase 3 and 7 activation followed by PARP cleavage, while DMAT induced nonapoptotic, programmed cell death. Human gliomas have different genetic alterations, which render them resistant to cell death, thus we evaluated their effects towards cells bearing distinctive alterations of major tumour suppressors: PT53 and PTEN. TBBi or ZKK-1 differentially induced cell death in two human malignant glioma cells. Interestingly, in contrast to ZKK-1, TBBi at doses toxic for glioma cells has no effect on nontransformed astrocytes, suggesting specificity toward tumour cells in cytotoxic action. The more bulky N-phenyl substituent in thiourea fragment of the molecule ZKK-1 reduced cytotoxic activity in pentabromobenzyl-series. Isothioureas carrying Cl or F substitutes on the phenyl ring showed much lower activity.

Collectively taken, the reported data support the idea that suitably modified tetrabromobenzene molecules may be powerful reagents counteracting CK2 tumourigenic potentials.

The study is supported by Ministry of Science and Higher Education (PBZ-MIN 014/P05/2004).

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