Combination of imatinib mesylate with lithium chloride and medroxyprogesterone acetate is highly active in Ishikawa endometrial carcinomain vitro

Abstract

ObjectiveThe 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.MethodsImatinib 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.ResultsAll 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).ConclusionThe 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.

Immunohistochemical Analysis for Therapeutic Targets and Prognostic Markers in Low-Grade Endometrial Stromal Sarcoma

“…Therefore, regardless of the status of c-kit expression, imatinib mesylate may be an effective targeting therapy for LGESS. Besides c-kit and PDGFR, c-Abl is also a tyrosine kinase that is targeted by imatinib mesylate 22 ; and some studies have reported the universal expression of c-Abl in patients with LGESS. 10,14 This fact further supports the possibility that imatinib mesylate may be an effective targeting therapy for LGESS.…”

Lithium chloride has a biphasic effect on prostate cancer stem cells and a proportional effect on midkine levels

“…Sections were examined with a JEM-1011 TEM (JEOL, Inc., Peabody, MA, USA). Photographs of stem cell and non-stem cell spheroids applied with the lowest (1 µM) and highest (500 µM) concentrations of LiCl were captured at several different magnifications (24).…”

“…The plates were inspected for colony (sphere) growth 1 week after initiation. The number of colonies within each well was counted under a microscope (Olympus BX-51; Olympus, Hamburg, Germany) and images of representative fields were captured (24).…”

“…Nucleocasettes were placed into the cell counter for 30-35 sec to measure PI fluorescence. Subsequently, cell counts were analyzed using the software and recorded (24).…”

“…After 15 min, 100 µl/well stop solution was added in order to inactivate the enzyme and detect blue color formation. Then, results were measured at a wavelength of 450 nm using an ELISA microplate reader within 3 min of stopping (24).…”