P08.49 Sensitivity of glioma cell lines and normal human cultured astrocytes to modified isothiourea derivative (ZKK-13) and Caseine Kinase II inhibitors

Abstract

Abstract Introduction: Glioblastoma multiforme (WHO grade IV) is the most aggressive primary brain tumour that is characterized by intratumoral heterogeneity, invasive growth and poor prognosis. The therapy of astroglial tumours remains still challenging. Promising group of compounds are derivatives of pentabromobenzylisothiouronium salt, which affect proliferation of some human cancer cells. Isothioureas are a class of amphiphilic compounds carrying a highly basic isothiourea group of pKa » 10. They exist in the protonated (cation) form, what is very important for molecular recognition of specific receptors. Second interesting class of compounds with a potential for cancer treatment are Caseine Kinase II (CK2) inhibitors. CK2 is an oncogenic protein kinase present in both the nucleus and cytoplasm of cells. The serine/threonine protein kinase CK2 modulates multiple signaling pathways involved in cell survival and function, and is therefore a promising drug target. The aim of this study was to evaluate the cytostatic effect of novel CK2 inhibitors and S-pentabromobenzylisothiourea derivative (ZKK-13) on cell lines of human glial tumours, as compared to normal human cultured astrocytes. Materials and Methods: We examined the cytostatic effect of selected modified isothiourea derivatives - pentabromobenzylisothioureas (ZKKs) including ZKK-13 and CK2 inhibitors against adult human glioblastoma cell line (T98G) and normal human cultured astrocytes. We analyzed cell viability (MTT metabolism assay), and conducted cell proliferation assay (Multisizer3; Beckman Coulter cell counter) after 24, 48 and 72 hours of incubation with investigated compounds. Results: In all experimental groups there was a marked decrease of a total cells number, especially after 48 and 72 hours of treatment. T98G cells treated with ZKK-13 showed a statistically significant decrease of proliferation rate at 10µM in comparison to the control cells. Inhibitor of kinase CK2 - 2- aminoethylamino-4,5,6,7- tetrabromo-1H- benzimidazole, appeared to be the most effective compound that exhibits a strong anti-proliferative effect on neoplastic astroglial cells in gliomas in vitro. Conclusions: The results show that CK2 inhibitors and S-pentabromobenzylisothiourea derivative have a potent antiproliferative efficacy against malignant glioma cells. It may offer a promising anti-tumour therapy, including treatment of glial cells-derived primary brain tumours.ACKNOWLEDGEMENT: The research was supported by the Foundation for the Development of Diagnostic and Therapy, Warsaw.