title: Combination of imatinib mesylate with lithium chloride and medroxyprogesterone acetate is highly active in Ishikawa endometrial carcinoma in vitro.
abstract: OBJECTIVE
  The aim of the study was to investigate whether lithium chloride and medroxyprogesterone acetate can potentiate the cytotoxicity of imatinib mesylate in human endometrial cancer in vitro and the effect of midkine in these therapies.
  
  
  METHODS
  Imatinib mesylate (50 µM), lithium chloride (100 µM), medroxyprogesterone acetate (200 µM) and their combination were applied to monolayer and three dimensional cultures of human Ishikawa endometrial cancer for 72 hours. The cell proliferation index, apoptotic index, caspase-3 and midkine levels, cell cycle distributions in monolayer cultures and cell ultrastructure in spheroid cultures were evaluated. Results were statistically analyzed using the Student's t-test.
  
  
  RESULTS
  All drug applications inhibited cell proliferation (p<0.05), however the combination were the effective groups for 72 hours (p<0.05). Interestingly, although the loss of efficiency was seen higly seen every 24 hours at single applications, the inhibition rates of the combination groups were almost same for 72 hours. In concordance with these results, the apoptotic index, caspase-3 levels (p<0.05), cell morphology and ultrastructure damages were much higher in the combination groups. Imatinib mesylate induced S-phase arrest, however other groups induced G0+G1-phase arrest at 24 hours and all groups induced G0+G1 arrest at 72 hours (p<0.05). Imatinib mesylate and imatinib mesylate with medroxyprogesterone acetate induced highest decrease in midkine levels, respectively (p<0.05).
  
  
  CONCLUSIONS
  The present study showed that the combination of imatinib mesylate with lithium chloride and medroxyprogesterone acetate is highly active in Ishikawa endometrial carcinoma in vitro and the inhibition of midkine involved in their mechanism of action against endometrium defense.
authors.affiliation: Department of Histology and Embryology, Istanbul University Faculty of Medicine, Istanbul, Turkey.
authors.forename: Ayhan
authors.initials: A
authors.lastname: Bilir
authors.forename: Mine
authors.initials: M
authors.lastname: Erguven
authors.forename: Ezgi
authors.initials: E
authors.lastname: Ermis
authors.forename: Mine
authors.initials: M
authors.lastname: Sencan
authors.forename: Nuray
authors.initials: N
authors.lastname: Yazihan