Abstract
Background
Gliomas account for approximately 40% of all central nervous system tumours. Tumour progression is considered to be related to uncontrolled intracellular signal transduction pathways, including proteins kinases. Kinase activation plays an important role in cell viability and proliferation. Thus, the development of novel protein kinase inhibitors might lead to beneficial therapies in cancers. Two class of compounds: Caseine Kinase II inhibitors and isothiourea derivatives (ZKKs) are promising drugs with anticancer activity. CK2 is serine-threonine kinase that plays an important role in key cellular processes, including the cell cycle and resistance to apoptosis. ZKKs, such as N,N, -dimethyl -S-2,3,4,5,6-pentabromobenzylisothiouronium bromides, also inhibit the activity of various proteins. In the previous studies we have documented the cytotoxic effect of selected CK2 inhibitors and ZKKs. The present study was undertaken to continue the research on anti-cancer effect of isothiourea derivatives and CK2 inhibitors on the cell lines of glia-derived human tumours of different histological malignancy.
Material and Methods
We examined the cytostatic effect of modified isothiourea derivatives and CK2 inhibitors against adult human glioblastoma cell line (T98G) and the cell line derived from low-grade subependymal giant cell astrocytoma - SEGA. We analyzed cell viability (MTT metabolism assay) and cell proliferation (Multisizer3 Beckman Coulter cell counter). Western blot was used to evaluate the expression of anti apoptotic proteins.
Results
In all experimental groups there was a marked decrease in a total cell number, especially after 48 hours of treatment. Isothiourea derivatives and CK2 inhibitors reduced cell viability both in high-grade malignant glioblastoma and low-grade SEGA cells. The viability of SEGA cells showed a statistically significant decrease after treatment with N,Ni -Diisopropyl-S-(2,3,4,5,6- pentabromobenzylisothiouronium bromide), even at a very low concentration of 1 μM. T98G cells treated with new CK2 inhibitor (4,5,6,7-tetrabromo N2-metylo- N2-hydroksyetylo-2-aminobenzimidazol) also showed a statistically significant decrease of viability rate in comparison to the control cultures. Western blot analyses revealed that modified isothiourea derivatives at a concentration of 10 μM caused a reduction in the level of anti apoptotic proteins in the cell lines of human glial tumours.
Conclusion
Caseine Kinase II inhibitors and isothiourea derivatives seem to be promising agents in anticancer therapy, including treatment of glioma-derived primary brain tumours. The inhibition suppression of antiapoptotic proteins seems to be involved in the therapeutic effect.
Acknowledgement
The research was supported by the Foundation for the Development of Diagnostic and Therapy, Warsaw