title: Schedule-dependent synergistic interaction between docetaxel and gefitinib in NSCLC cell lines regardless of the mutation status of EGFR and KRAS and its molecular mechanisms.
abstract: BACKGROUND
  Tyrosine-kinase inhibitors (TKIs) and chemotherapy had different pharmacological mechanisms and therefore combined administration of TKIs and chemotherapy agents may have synergy. Our research aimed at exploring the cytotoxic interactions between gefitinib and docetaxel with different concentrations for non-small-cell lung cancer cell lines, and furthermore, the mechanisms underlying the cytotoxic synergism.
  
  
  METHODS
  NCI-H1650 [epidermal growth factor receptor (EGFR) mutation and KRAS wild-type], NCI-H292 (EGFR wild-type and KRAS wild-type) and A549 (EGFR wild-type and KRAS mutation) cell lines were treated with docetaxel and/or gefitinib. Cytotoxic interactions, cell cycle distribution and cell signal pathway were analyzed, respectively.
  
  
  RESULTS
  Cytotoxic interactions between docetaxel and gefitinib were dose-dependent and sequence-dependent in all these three cell lines. Docetaxel followed by gefitinib treatment was optimum regimen regardless of the mutation status of EGFR and KRAS. KRAS mutation and EGFR wild-type predicted insensitive to gefitinib and docetaxel combined treatment as well as gefitinib alone. G1 arrest was inconsistently associated with combination index (CI). However, apoptosis induction was schedule-dependent and can explain the synergism completely. Mitogen-activated protein kinase (MAPK) phosphorylation ratio was also schedule-dependent and positively correlated with CI.
  
  
  CONCLUSIONS
  Cytotoxic interactions between docetaxel and gefitinib were sequence-dependent regardless of the mutation status of EGFR and KRAS. Cell characteristic, apoptosis induction and MAPK phosphorylation but not cell cycle change may explain the molecular mechanisms of synergism.
authors.affiliation: Department of Respiratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People's Republic of China, jiangyanwen2009@163.com.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Jiang
authors.forename: Qing
authors.initials: Q
authors.lastname: Yuan
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Fang
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000008:administration & dosage*; D043823:Taxoids / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D043823:Taxoids; D000077143:Docetaxel; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000077156:Gefitinib
references.citation: Cancer Biol Ther. 2003 Nov-Dec;2(6):670-6
references.pmid: 14688474
references.citation: Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):839-44
references.pmid: 16467097
references.citation: Clin Lung Cancer. 2006 May;7(6):385-8
references.pmid: 16800963
references.citation: Science. 2004 Aug 20;305(5687):1163-7
references.pmid: 15284455
references.citation: J Clin Oncol. 2004 Mar 1;22(5):785-94
references.pmid: 14990633
references.citation: Clin Lung Cancer. 2007 Feb;8 Suppl 2:S61-7
references.pmid: 17382026
references.citation: Clin Cancer Res. 2007 Jun 1;13(11):3413-22
references.pmid: 17545550
references.citation: Pharmacol Rev. 2006 Sep;58(3):621-81
references.pmid: 16968952
references.citation: Ann Oncol. 2009 Apr;20(4):696-702
references.pmid: 19088172
references.citation: Clin Cancer Res. 2002 Jul;8(7):2091-9
references.pmid: 12114408
references.citation: N Engl J Med. 2009 Sep 3;361(10):947-57
references.pmid: 19692680
references.citation: Mol Pharmacol. 2008 Apr;73(4):1290-300
references.pmid: 18187583
references.citation: N Engl J Med. 2005 Jul 14;353(2):123-32
references.pmid: 16014882
references.citation: Lung Cancer. 2011 Sep;73(3):274-82
references.pmid: 21277645
references.citation: Oncol Rep. 2014 Jan;31(1):183-8
references.pmid: 24247637
references.citation: J Clin Oncol. 2005 Apr 10;23(11):2445-59
references.pmid: 15753456
references.citation: Clin Lab. 2012;58(5-6):551-61
references.pmid: 22783588
references.citation: CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
references.pmid: 19474385
references.citation: J Clin Oncol. 2005 Sep 1;23(25):5900-9
references.pmid: 16043828
references.citation: J Clin Oncol. 2007 Apr 20;25(12):1545-52
references.pmid: 17442998
references.citation: N Engl J Med. 2010 Jun 24;362(25):2380-8
references.pmid: 20573926
references.citation: J Clin Oncol. 1998 Feb;16(2):651-7
references.pmid: 9469354
references.citation: J Immunol Methods. 1983 Dec 16;65(1-2):55-63
references.pmid: 6606682
references.citation: Clin Lung Cancer. 2007 Nov;8(9):548-53
references.pmid: 18186959
references.citation: Clin Lung Cancer. 2011 Jan;12(1):56-61
references.pmid: 21273181
references.citation: Anticancer Res. 2010 Dec;30(12):5121-8
references.pmid: 21187500
references.citation: J Clin Oncol. 2005 Nov 1;23(31):8081-92
references.pmid: 16204011
references.citation: Nat Rev Cancer. 2007 Mar;7(3):169-81
references.pmid: 17318210
references.citation: Cancer Res. 2006 Jan 15;66(2):981-8
references.pmid: 16424033
references.citation: J Clin Oncol. 2010 Nov 1;28(31):4769-77
references.pmid: 20921461
references.citation: J Thorac Oncol. 2007 Aug;2(8):715-21
references.pmid: 17762337
references.citation: Oncol Rep. 2010 Nov;24(5):1141-6
references.pmid: 20878103
references.citation: J Cell Biochem. 2006 Aug 1;98(5):1284-95
references.pmid: 16514644
references.citation: N Engl J Med. 2005 Jul 14;353(2):133-44
references.pmid: 16014883
references.citation: J Clin Oncol. 2004 Mar 1;22(5):777-84
references.pmid: 14990632