title: A new strategy in the treatment of chemoresistant lung adenocarcinoma via specific siRNA transfection of SRF, E2F1, Survivin, HIF and STAT3.
abstract: OBJECTIVE
  According to the actual treatment strategies of lung cancer, the current therapeutic regimen is an individualized, multidisciplinary concept. The development of chemoresistance in the last decade represents the most important obstacle to an effective treatment. In our study, we examined a new therapeutic alternative in the treatment of multiresistant lung adenocarcinoma via siRNA-specific transfection of six crucial molecules involved in lung carcinogenesis [serum response factor(SFR), E2F1, Survivin, hypoxia inducible factor1 (HIF1), HIF2 and signal transducer and activator of transcription (STAT3)].
  
  
  METHODS
  Three chemoresistant A549 adenocarcinoma cells were cultured under standard conditions at 37°C and 5% CO2. The chemoresistance against Vinflunine, Vinorelbine and Methotrexate was induced artificially. The A549 cells were transfected for 2 h at 37°C with specific siRNA targeting SRF, E2F1, Survivin, HIF1, HIF2 and STAT3 in a non-viral manner. The efficiency of siRNA silencing was evaluated via quantitative real-time polymerase chain reaction, whereas the surviving cells after siRNA transfection as predictor factor for tumoural growth were analysed with a CASY cell counter 3 days after transfection.
  
  
  RESULTS
  The response of the chemotherapeutic resistant adenocarcinoma cells after siRNA transfection was concentration-dependent at both 25 and 100 nM. The CASY analysis showed a very effective suppression of adenocarcinoma cells in Vinorelbine, Vinflunine and Methotrexate groups, with significantly better results in comparison with the control group.
  
  
  CONCLUSIONS
  In our study, we emphasized that siRNA interference might represent a productive platform for further research in order to investigate whether a new regimen in the treatment of multiresistant non-small-cell lung cancer could be established in vivo in the context of a multimodal cancer therapy.
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University Medical Center Tuebingen, Tuebingen, Germany.
authors.forename: Mircea Gabriel
authors.initials: MG
authors.lastname: Stoleriu
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University Medical Center Tuebingen, Tuebingen, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Steger
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University Medical Center Tuebingen, Tuebingen, Germany.
authors.forename: Migdat
authors.initials: M
authors.lastname: Mustafi
authors.affiliation: Department of Cell Biology, School of Biosciences, University of Kent, Canterbury, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Michaelis
authors.affiliation: Department of Pediatric Cancer and Virus Research, Frankfurt am Main, Germany.
authors.forename: Jindrich
authors.initials: J
authors.lastname: Cinatl
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University Medical Center Tuebingen, Tuebingen, Germany.
authors.forename: Wilke
authors.initials: W
authors.lastname: Schneider
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University Medical Center Tuebingen, Tuebingen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Nolte
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University Medical Center Tuebingen, Tuebingen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Kurz
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University Medical Center Tuebingen, Tuebingen, Germany.
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Wendel
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University Medical Center Tuebingen, Tuebingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schlensak
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University Medical Center Tuebingen, Tuebingen, Germany tobias.walker@med.uni-tuebingen.de.
authors.forename: Tobias
authors.initials: T
authors.lastname: Walker
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000628:therapy*; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D050687:E2F1 Transcription Factor / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics / Q000628:therapy*; D008727:Methotrexate / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics*; D026362:Serum Response Factor / Q000235:genetics*; D000077022:Survivin; D014162:Transfection / Q000379:methods; D014747:Vinblastine / Q000031:analogs & derivatives / Q000494:pharmacology; D000077235:Vinorelbine; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D050687:E2F1 Transcription Factor; D051793:Hypoxia-Inducible Factor 1; D051034:Inhibitor of Apoptosis Proteins; D008727:Methotrexate; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D026362:Serum Response Factor; D000077022:Survivin; D014747:Vinblastine; D000077235:Vinorelbine; D000099162:Endothelial PAS Domain-Containing Protein 1; C107489:BIRC5 protein, human; C493753:E2F1 protein, human; C476858:SRF protein, human; C494086:STAT3 protein, human; C111217:vinflunine
keywords: Chemoresistance; Multimodality concept; NSCLC; Target molecules; siRNA