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Clinical & Experimental Metastasis
Published in: Clinical & Experimental Metastasis 6/2015

01-08-2015 | Research Paper

Targeting Notch signaling by γ-secretase inhibitor I enhances the cytotoxic effect of 5-FU in gastric cancer

Authors: Hyun-Woo Lee, Seok-Jun Kim, Il Ju Choi, Jaewhan Song, Kyung-Hee Chun

Published in: Clinical & Experimental Metastasis | Issue 6/2015

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Abstract

Current medication for gastric cancer patients has a low success rate and the patients develop rapid tolerance to these drugs. Therefore, the development of new regimens is desired. In this study, we determined that Notch-signaling-related genes were overexpressed and activated in gastric cancer patients and gastric cancer cell lines. According to recent studies, γ-secretase inhibitors (GSIs), which function as Notch signaling inhibitors, could be used as therapeutic drugs in cancer. We demonstrated that GSI I (cbz-IL-CHO) is the most effective GSI in gastric cancer cells. We also determined the cell survival signaling-related proteins that were affected by GSI I. The levels of phosphorylated AKT were significantly decreased upon GSI I treatment, and constitutively activated myristoylated AKT completely blocked GSI I-induced apoptosis and cell survival, suggesting that inhibition of AKT signaling is critical for GSI I-mediated effects in gastric cancer cells. In order to maximize the effects and safety of GSI I, a combination treatment with GSI I and 5-FU was performed. Inhibition of gastric cancer cell proliferation with the combination treatment was significantly better than that with the single treatment. All phosphorylated forms of AKT, p44/42, JNK, and p38 were drastically changed by the combination treatment. Orthotopically transplanted gastric tumor burdens in mice were reduced using the combined treatment. The outcomes of this study clearly demonstrated the therapeutic potential of GSI I in gastric cancer, as well as the greater efficacy of the combined treatment of GSI I with 5-FU. Therefore, we suggest that further clinical trials examining the potential of combined GSI I and 5-FU treatment in gastric cancer patients be undertaken.
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Metadata
Title
Targeting Notch signaling by γ-secretase inhibitor I enhances the cytotoxic effect of 5-FU in gastric cancer
Authors
Hyun-Woo Lee
Seok-Jun Kim
Il Ju Choi
Jaewhan Song
Kyung-Hee Chun
Publication date
01-08-2015
Publisher
Springer Netherlands
Published in
Clinical & Experimental Metastasis / Issue 6/2015
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI
https://doi.org/10.1007/s10585-015-9730-5

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