title: Antagonist activity of the antipsychotic drug lithium chloride and the antileukemic drug imatinib mesylate during glioblastoma treatment in vitro.
abstract: OBJECTIVE
  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.
authors.affiliation: a İstanbul Faculty of Medicine, Departmentof Neurosurgery , İstanbul University , İstanbul , Turkey.
authors.forename: Yavuz
authors.initials: Y
authors.lastname: Aras
authors.affiliation: b Faculty of Engineering and Vocational School of Health Sciences , İstanbul Aydın University , İstanbul , Turkey.
authors.forename: Mine
authors.initials: M
authors.lastname: Erguven
authors.affiliation: c Department of Immunology , Prof. Dr. Aziz Sancar Institute of Experimental Medicine, İstanbul University , İstanbul , Turkey.
authors.forename: Esin
authors.initials: E
authors.lastname: Aktas
authors.affiliation: d Faculty of Medicine, Department of Pathophysiology , Ankara University , Ankara , Turkey.
authors.forename: Nuray
authors.initials: N
authors.lastname: Yazihan
authors.affiliation: e Emine-Bahaeddin Nakıboğlu Faculty of Medicine, Department of Histology and Embryology , Zirve University , Gaziantep , Turkey.
authors.forename: Ayhan
authors.initials: A
authors.lastname: Bilir
mesh_terms: D018692:Antimanic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051401:Aquaporin 4 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D004338:Drug Combinations; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D018021:Lithium Chloride / Q000494:pharmacology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D013997:Time Factors
chemical_list: D018692:Antimanic Agents; D000970:Antineoplastic Agents; D051401:Aquaporin 4; D053148:Caspase 3; D000242:Cyclic AMP; D004338:Drug Combinations; D066246:ErbB Receptors; D000068877:Imatinib Mesylate; D018021:Lithium Chloride; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D020796:Receptor, Platelet-Derived Growth Factor alpha; C496030:AQP4 protein, human; C512478:EGFR protein, human; C421109:multidrug resistance-associated protein 1
keywords: Antagonism; Glioblastoma; Imatinib mesylate; Lithium chloride; Midkine