The mechanism of vinorelbine-induced apoptosis and radiosensitization in lung cancer cells

Abstract

The standard treatment regimen for patients who are diagnosed with unsectable locally advanced stage III non-small cell lung cancer (NSCLC) is platinum-based doublet regimen concurrent chemoradiotherapy (CCRT) Many doctors have expressed an interest in identifying more active and better tolerated single agent for the treatment We reviewed the records of 68 patients with stage III NSCLC: 42 patients received VNR-based CCRT and 26 were treated with radiation alone There was response rate of 66 7% in patients with CCRT which was better than the patients with radiation alone (30 8%; P <0 001) This study investigated the molecular cytotoxic mechanism of VNR and synergistic effects of VNR-based CCRT First we identify the molecular mechanisms underlying growth inhibition as well as apoptosis in VNR-treated lung adenocarcinoma cells Treatment with VNR caused mitotic prometaphase arrest accompanied by cell apoptosis VNR sequentially induced mitochondrial transmembrane potential (MTP) loss and caspase-dependent apoptosis following myeloid cell leukemia (Mcl) 1 downregulation Prolonged activation of c-Jun N-terminal kinase (JNK) was required for VNR-induced apoptosis but not cell cycle arrest VNR caused glutathione/reactive oxygen species (ROS) imbalance and inhibiting ROS prevented prolonged JNK activation decreased Mcl-1 levels MTP loss and apoptosis VNR induced aberrant JNK-regulated DNA damage in prometaphase These results demonstrate an essential role of ROS in VNR-induced aberrant JNK-mediated Mcl-1 downregulation and DNA damage followed by mitochondrial dysfunction-related apoptosis but not mitotic arrest Second human lung adenocarcinoma cells were used in this study to investigate the molecular effects of glucosylceramide synthase inhibition on VNR-based CCRT 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

Date of Award	2014 Aug 22
Original language	English
Supervisor	Wu-Chou Su (Supervisor)