KMID : 0358420100530030243
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Korean Journal of Obstetrics and Gynecology 2010 Volume.53 No. 3 p.243 ~ p.253
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Anti-proliferative effect in epithelial ovarian cancer cells by MEK Inhibitor AZD6244
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Yu Shin-Ae
Kim Seong-Chol Jo Mu-Seong Suh Dong-Soo Kim Ki-Hyung Yoon Man-Soo
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Abstract
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Objective: The objectives of this study were to determine the efficacy of AZD6244, a potent, selective MEK inhibitor, in epithelial ovarian cancer (EOC) cells and to determine the enhanced cell death by combined treatment of paclitaxel and AZD6244.
Methods: EOC cells were treated with tenfold dilutions of AZD6244 (0.1 to 10 ¥ìM) for 24, 48 and 72 hours. Cell viability was determined by the CellTiter 96 AQueous One Solution Cell Proliferation Assay. The apoptotic cascade was assessed by Caspase-Glo assays. ERK activation was evaluated by Western blot analyses. Cytokine profiling was performed from culture supernatants using the Luminex 200 system.
Results: In vitro cell viability showed that ovarian cancer cells with high p-ERK activities (A2780, R454, 01-28) exhibited significant growth inhibition. Cells with low p-ERK activities (R182, CP70), however, were resistant to AZD6244. Caspase-3 was not activated during AZD6244-induced growth inhibition. AZD6244 significantly inhibited p-ERK1/2 in both cell types regardless of constitutive levels of p-ERK. Proinflammatory cytokines including IL-6, IL-8, MCP-1 and GM-CSF were significantly decreased. Paclitaxel activated the p-ERK levels in paclitaxel-resistant R182 cells with low basal p-ERK level. MEK inhibition by AZD6244 enhanced paclitaxel-induced apoptosis significantly in R182 cells.
Conclusion: These results demonstrate that AZD6244 has a potent growth inhibitory effect in ovarian cancer cells with high p-ERK activities. In addition, targeted inhibition of the extracellular signal-regulated kinase pathway with AZD6244 can enhance the anti-tumor efficacy of the cytotoxic paclitaxel.
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KEYWORD
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Ovarian cancer, MEK inhibitor, AZD6244, Paclitaxel
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