Abstract
Gastrointestinal cancers frequently exhibit mutational activation of the Ras/MAPK pathway, which is implicated in resistance to ionizing radiation (IR) and chemotherapy. Concurrent radiotherapy and 5-fluorouracil (5-FU) based chemotherapy is commonly used for treatment of gastrointestinal malignancies. We previously reported radiosensitization with selumetinib, an inhibitor of MEK1/2. The purpose of the current study was to evaluate if selumetinib could enhance radiosensitivity induced by 5-FU. Clonogenic survival assays were carried out with the HT29 (colorectal), HCT116 (colorectal), and MiaPaca-2 (pancreatic) cell lines using pre-IR treatment with selumetinib, 5-FU and 5-FU+selumetinib. Cell proliferation was determined using a tetrazolium conversion assay. Mitotic catastrophe and DNA repair were analyzed using immunocytochemistry. Flow cytometry was used to analyze cell cycle and apoptosis. Growth delay was used to determine effects of 5-FU+selumetinib on in vivo tumor radiosensitivity. Pre-IR treatment with 5-FU+selumetinib significantly decreased clonogenic survival compared with either agent alone. Dose modifying factors at a surviving fraction of 0.1 for 5-FU+selumetinib was 1.78, 1.52, and 1.3 for HT29, HCT116, and MiaPaca-2, respectively. Cell proliferation was decreased by treatment with selumetinib+5-FU as compared with single agent treatment regardless of treatment sequencing. Enhancement of 5-FU cytotoxicity and 5-FU mediated radiosensitization with selumetinib treatment was accompanied by an increase in mitotic catastrophe and apoptosis, and reductions in Stat3 phosphorylation and survivin expression. In vivo, an additive growth delay was observed with 5-FU+selumetinib+3Gy versus 5-FU+3Gy and selumetinib alone. These data suggest that selumetinib can be used with 5-FU to augment radiation response.
Highlights
One of the hallmarks of cancer cells is the up-regulation of cellular pathways that provide survival advantages by promoting proliferation and/or decreasing cell death [1]
Selumetinib (AZD6244, ARRY-142886), a selective inhibitor of MEK1/2, has been shown to have single agent efficacy in a variety of human tumor cell lines, with greater single agent efficacy observed in BRaf and KRas mutant cell lines [2]
To determine if selumetinib could enhance the radiation sensitization observed with 5fluorouracil, we performed clonogenic survival assays with three tumor cells lines
Summary
One of the hallmarks of cancer cells is the up-regulation of cellular pathways that provide survival advantages by promoting proliferation and/or decreasing cell death [1]. One such pathway is the Ras/Raf/mitogen activated protein kinase (MAPK)/extracellular signalregulated kinase (ERK) pathway, which is involved in cell proliferation, differentiation, apoptosis, and survival. We and others have previously shown that inhibition of signaling via the Ras/MAPK pathway enhances sensitivity to radiation [7,8,9]. Inhibition of the Ras/MAPK pathway has been exploited as a means to sensitize tumors cells to cytotoxic chemotherapy [5, 6]
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