title: Schedule-dependent cytotoxicity of sunitinib and TRAIL in human non-small cell lung cancer cells with or without EGFR and KRAS mutations.
abstract: BACKGROUND
  Non-small cell lung cancer (NSCLC) patients who do initially respond to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) may eventually develop resistance, which may at least partly be due to the acquisition of a secondary EGFR mutation (T790M). Additionally, it has been found that KRAS mutations may serve as poor prognostic biomarkers. Here, we aimed at establishing a suitable treatment regimen for the multi-target TKI sunitinib and the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in NSCLC-derived cells with or without EGFR and KRAS mutations.
  
  
  METHODS
  Four NSCLC-derived cell lines with or without EGFR and KRAS mutations were exposed to different sunitinib and TRAIL treatment regimens. Alterations in cell viability, cell cycle distribution, apoptosis, phosphorylation of AKT and expression of the death receptors DR4 and DR5 were evaluated using CCK8, flow cytometry and Western blotting assays, respectively.
  
  
  RESULTS
  A synergistic cytotoxic effect was observed in all four cell lines treated with sunitinib (1 nM) followed by TRAIL (100 ng/ml), as well as after simultaneous treatment with both agents. We found that sunitinib enhances TRAIL-induced G0/G1-phase cell cycle arrest and blocks TRAIL-triggered activation of AKT as the underlying mechanism. In contrast, we observed antagonistic effects when sunitinib was administered after TRAIL to the cell lines tested. A decreased DR4 and DR5 expression was found to be correlated with this antagonism.
  
  
  CONCLUSIONS
  From our data we conclude that administration of sunitinib followed by TRAIL, as well as a simultaneous administration of both agents, serve as favorable treatment regimens for NSCLC-derived cells, irrespective of their EGFR and/or KRAS mutation status.
authors.affiliation: Department of Respiratory Medicine, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, People's Republic of China.
authors.forename: Yong-Xia
authors.initials: YX
authors.lastname: Bao
authors.affiliation: Department of Laboratory, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, People's Republic of China.
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Zhao
authors.affiliation: Dental Hospital, The First Affiliated Hospital of Harbin Medical University, 150001, 23 Youzheng Road, Nangang District, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Hong-Bin
authors.initials: HB
authors.lastname: Deng
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, 157 Baojian Rd, Harbin, 150081, Heilongjiang, People's Republic of China.
authors.forename: Chang-Lian
authors.initials: CL
authors.lastname: Lu
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Dental Hospital, The First Affiliated Hospital of Harbin Medical University, 150001, 23 Youzheng Road, Nangang District, Harbin, Heilongjiang, People's Republic of China.
authors.forename: Xing
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, People's Republic of China. dengdoctor@126.com.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Deng
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D018773:Genes, erbB-1; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011758:Pyrroles / Q000008:administration & dosage*; D000077210:Sunitinib; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage*
chemical_list: D007211:Indoles; C117307:KRAS protein, human; D011758:Pyrroles; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D000077210:Sunitinib
keywords: Gene mutation; Non-small cell lung cancer; Sequential treatment; Sunitinib; TRAIL