Antagonist activity of the antipsychotic drug lithium chloride and the antileukemic drug imatinib mesylate during glioblastoma treatment in vitro |
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| Authors: | Yavuz Aras Esin Aktas Nuray Yazihan Ayhan Bilir |
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| Affiliation: | 1. ?stanbul Faculty of Medicine, Departmentof Neurosurgery, ?stanbul University, ?stanbul, Turkey;2. Department of Immunology, Prof. Dr. Aziz Sancar Institute of Experimental Medicine, ?stanbul University, ?stanbul, Turkey;3. Faculty of Medicine, Department of Pathophysiology, Ankara University, Ankara, Turkey;4. Emine-Bahaeddin Nak?bo?lu Faculty of Medicine, Department of Histology and Embryology, Zirve University, Gaziantep, Turkey |
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| Abstract: | Objectives: Glioblastoma (GBM), the most common primary tumour of the central nervous system, is characterised by a high malignancy and poor prognosis. The aims of this study were to investigate whether the combination of imatinib mesylate (IM) and lithium chloride (LiCl) exhibited a synergistic effect in treatment and to determine whether midkine (MK) affected the fate of this treatment in vitro.Methods: Monolayer and spheroid cultures of the T98G human GBM cell line were treated with an IM and LiCl combination for 72 h. The cell proliferation index, apoptotic index, cell cycle distribution, apoptotic and anti-apoptotic protein levels, and cAMP level as well as the cellular morphology and ultrastructure were evaluated.Results: All applications inhibited cell proliferation and induced apoptosis. The most substantial decreases in cell proliferation and the caspase-3, epidermal growth factor receptor (EGFR), platelet derived growth factor receptor-alpha (PDGFR-α), multidrug resistance protein-1 (MRP-1), aquaporin-4 (AQP-4) and cAMP levels were induced by the LiCl treatment, which exhibited more pronounced effects compared with the combination treatment. LiCl was less effective in decreasing the MK and B cell lymphoma-2 (Bcl-2) levels compared with the combination treatment. The most substantial decrease in the p170 levels was identified following the combination treatment, whereas IM induced the second greatest decrease. LiCl alone had no effect on the p170 levels. IM induced the most substantial decrease in the phospho-glycogen synthase kinase 3-beta (p-GSK-3β)/glycogen synthase kinase 3-beta (GSK-3β) ratio, and LiCl induced the second most substantial decrease. Both LiCl and the combination treatment induced G2 + M arrest, whereas IM induced G0 + G1 arrest after 72 h of exposure. An apoptotic appearance and autophagic vacuoles were commonly identified in the LiCl, combination and IM groups, respectively.Conclusions: The combination of IM and LiCl exhibited an antagonist effect, and MK had a role at this antagonism. |
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| Keywords: | Imatinib mesylate Lithium chloride Midkine Glioblastoma Antagonism |
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