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

 Hyun-Woo Lee  ;  Seok-Jun Kim  ;  Il Ju Choi  ;  Jaewhan Song  ;  Kyung-Hee Chun 
 CLINICAL & EXPERIMENTAL METASTASIS, Vol.32(6) : 593-603, 2015 
Journal Title
Issue Date
Amyloid Precursor Protein Secretases/antagonists & inhibitors ; Animals ; Antimetabolites, Antineoplastic/pharmacology ; Apoptosis/drug effects* ; Blotting, Western ; Cell Adhesion/drug effects ; Cell Cycle/drug effects ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Drug Synergism* ; Female ; Fluorouracil/pharmacology* ; Gene Expression Regulation, Neoplastic/drug effects* ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Oligopeptides/pharmacology* ; Phosphorylation/drug effects ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Receptors, Notch/antagonists & inhibitors* ; Receptors, Notch/genetics ; Receptors, Notch/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/drug effects ; Stomach Neoplasms/drug therapy* ; Stomach Neoplasms/metabolism ; Stomach Neoplasms/pathology ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
Gastric cancer ; GSI ; 5-FU ; Combination therapy
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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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Seok Jun(김석준)
Chun, Kyung Hee(전경희) ORCID logo https://orcid.org/0000-0002-9867-7321
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