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

  • Authors:
    • Bozena Kaminska
    • Aleksandra Ellert-Miklaszewska
    • Agata Oberbek
    • Pawel Wisniewski
    • Beata Kaza
    • Malgorzata Makowska
    • Maria Bretner
    • Zygmunt Kazimierczuk
  • View Affiliations

  • Published online on: November 1, 2009     https://doi.org/10.3892/ijo_00000424
  • Pages: 1091-1100
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Abstract

Malignant gliomas are highly resistant to current therapeutic approaches due to genetic alterations rendering them resistant to cell death. CK2, a ubiquitous and constitutively active serine/threonine kinase, frequently elevated in tumors, contributes to enhanced cell proliferation and resistance to apoptosis. Inhibition of CK2 expression or treatment with inhibitors of CK2 affected survival or induced apoptosis in various cancer cells. Here we compared cytotoxic effects of well-known and new CK2 inhibitors: 4,5,6,7-tetrabromo-1H-benzotriazole (TBB), 4,5,6,7-tetrabromo-1H-benzimidazole (TBI), 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), the related 3-(4,5,6,7-tetrabromo-1H-benzimidazol-1-yl)propan-1-ol (MB001), 3-(4,5,6,7-tetrabromo-1H-1,2,3-benzotriazol-1-yl) propan-1-ol (MB002), 3-(4,5,6,7-tetrabromo-2H-1,2,3-benzotriazol-2-yl)propan-1-ol (MB003) and also structurally similar to above compounds pentabromobenzylisothiourea (ZKK1) and its derivatives (ZKK2-8) on cultured malignant glioma cells. TBI, ZKK1 and MB001-3 were more effective than TBB in inducing growth arrest and cell death in glioma cells. TBI and ZKK1 strongly induced apoptotic death involving caspase 3 and 7 activation followed by PARP cleavage. DMAT strongly upregulated the expression of cytotoxic ligand and its receptor Fas. Structural modifications of ZKK1 largely affected its efficacy: exchange of Br- to Cl- or F-substituents on the pentabromophenyl ring and inclusion of the bulky N-phenyl substituent in thiourea fragment of ZKK1 diminished cytotoxic activity, while N-substitution with short alkyl groups or an allyl group had opposite effects. Interestingly, TBI at moderate dose did not affect viability of non-transformed astrocytes, suggesting some specificity toward tumor cells in cytotoxic action. TBI, DMAT and ZKK1-induced apoptosis associated with caspase cascade activation in human malignant glioblastoma cells with mutated PT53 and PTEN genes. The reported data demonstrate that suitably modified polybromobenzene molecules exhibit a significant cytotoxic potential towards malignant glioblastoma cells.

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November 2009
Volume 35 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Kaminska B, Ellert-Miklaszewska A, Oberbek A, Wisniewski P, Kaza B, Makowska M, Bretner M and Kazimierczuk Z: Efficacy and mechanism of anti-tumor action of new potential CK2 inhibitors toward glioblastoma cells. Int J Oncol 35: 1091-1100, 2009.
APA
Kaminska, B., Ellert-Miklaszewska, A., Oberbek, A., Wisniewski, P., Kaza, B., Makowska, M. ... Kazimierczuk, Z. (2009). Efficacy and mechanism of anti-tumor action of new potential CK2 inhibitors toward glioblastoma cells. International Journal of Oncology, 35, 1091-1100. https://doi.org/10.3892/ijo_00000424
MLA
Kaminska, B., Ellert-Miklaszewska, A., Oberbek, A., Wisniewski, P., Kaza, B., Makowska, M., Bretner, M., Kazimierczuk, Z."Efficacy and mechanism of anti-tumor action of new potential CK2 inhibitors toward glioblastoma cells". International Journal of Oncology 35.5 (2009): 1091-1100.
Chicago
Kaminska, B., Ellert-Miklaszewska, A., Oberbek, A., Wisniewski, P., Kaza, B., Makowska, M., Bretner, M., Kazimierczuk, Z."Efficacy and mechanism of anti-tumor action of new potential CK2 inhibitors toward glioblastoma cells". International Journal of Oncology 35, no. 5 (2009): 1091-1100. https://doi.org/10.3892/ijo_00000424