Journal
CANCER LETTERS
Volume 349, Issue 2, Pages 144-151Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2014.04.005
Keywords
NSCLC; CCRT; Vinorelbine; JNK; Ceramide
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Funding
- National Cheng Kung University Hospital in Taiwan [NCKUH-10103035]
- National Science Council, Taiwan [NSC100-2320-B-006-009-MY3]
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The standard treatment regimen for patients diagnosed with non-small cell lung cancer (NSCLC) with locally advanced stage HI disease is concurrent chemoradiotherapy (CCRT). This study investigated the molecular effects of vinca alkaloid vinorelbine (VNR)-based CCRT. We reviewed the records of 68 patients with stage III NSCLC: 42 patients received VNR-based CCRT, and 26 were treated with radiation alone. Human lung adenocarcinoma cells were used in this study to investigate the molecular effects of glucosylceramide synthase inhibition on VNR-based CCRT. There was response rate of 66.7% with CCRT, which was better than the response rate observed with radiation alone (30.8%; P < 0.001). CCRT caused an increase in cell cycle arrest at G(2)/M phase accompanied by apoptosis. Oxidative c-Jun N-terminal kinase (INK) activation was involved in the increased apoptosis levels but not the cell cycle arrest. CCRT also induced an increase in ceramide accompanied by a decrease in glucosylceramide that was positively correlated with the cytotoxic effects. Pharmacologically inhibiting glucosylceramide synthase facilitated VNR- and CCRT-induced apoptosis by promoting the JNK pathway. Inhibiting glucosylceramide synthase facilitates the radiosensitizing effects of VNR by promoting JNK-mediated apoptosis in lung adenocarcinoma cells. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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