title: Inhibiting glucosylceramide synthase facilitates the radiosensitizing effects of vinorelbine in lung adenocarcinoma cells.
abstract: The standard treatment regimen for patients diagnosed with non-small cell lung cancer (NSCLC) with locally advanced stage III 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 G2/M phase accompanied by apoptosis. Oxidative c-Jun N-terminal kinase (JNK) 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.
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Division of Hemato-Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Wei-Hsin
authors.initials: WH
authors.lastname: Chiu
authors.affiliation: Department of Radiation Oncology, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Helen Hai-Wen
authors.initials: HH
authors.lastname: Chen
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
authors.forename: Jang-Yang
authors.initials: JY
authors.lastname: Chang
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Sheng-Jie
authors.initials: SJ
authors.lastname: Luo
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Division of Hemato-Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address: Sunnysu@mail.ncku.edu.tw.
authors.forename: Wu-Chou
authors.initials: WC
authors.lastname: Su
authors.affiliation: Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address: cflin@mail.ncku.edu.tw.
authors.forename: Chiou-Feng
authors.initials: CF
authors.lastname: Lin
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy*; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism; D059248:Chemoradiotherapy; D005260:Female; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D012189:Retrospective Studies; D014747:Vinblastine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000077235:Vinorelbine
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002518:Ceramides; D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species; D014747:Vinblastine; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D000077235:Vinorelbine
keywords: CCRT; Ceramide; JNK; NSCLC; Vinorelbine