title: 5-aminolaevulinic acid/photo-dynamic therapy and gefitinib in non-small cell lung cancer cell lines: a potential strategy to improve gefitinib therapeutic efficacy.
abstract: OBJECTIVE
  Often, non-small cell lung cancers (NSCLC) respond only poorly to the tyrosine kinase inhibitor (TKI) gefitinib, which targets the epidermal growth factor receptor (EGFR), these poor responders EGFRs lacking activating mutations. In this study, we have attempted to improve TKI response of NSCLC cell lines (A549 and H1299) devoid of EGFR mutations, by combination of gefitinib and 5-ALA/photodynamic therapy (PDT).
  
  
  METHODS
  Cells of the two lines were incubated with gefitinib (from 0.5 to 50 mm, for 48 h) then irradiated at doses ranging from 4 to 20 J/cm(2) ; 5-ALA concentration and incubation time were kept constant (1 mm for 3 h). We analysed cell viability, colony-forming efficiency, cell cycle parameters, proteasome and NF-κB activity and expression patterns of specific proteins, after individual or combined treatments.
  
  
  RESULTS
  Effects (antagonistic, additive or synergistic) of combination treatment were evaluated using a predictive model (combination index) for expected interactive effects and results are consistent with mutual potentiation exceeding simple additivity. Investigation of molecular mechanisms underlying cytotoxic effects indicated that combination treatment impaired proteasome function, inhibited NF-κB transcriptional activity and hampered AKT pro-survival signalling.
  
  
  CONCLUSIONS
  The results of this study show that poor response of cells devoid of EGFR activating mutations to TKIs, can be overcome by combining gefitinib with 5-ALA/photodynamic therapy (PDT).
authors.affiliation: Department of Molecular Medicine and Health Biotechnology, University Federico II, Naples, 80131, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Postiglione
authors.forename: A
authors.initials: A
authors.lastname: Chiaviello
authors.forename: S M
authors.initials: SM
authors.lastname: Aloj
authors.forename: G
authors.initials: G
authors.lastname: Palumbo
mesh_terms: D000622:Aminolevulinic Acid / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D017319:Photosensitizing Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000622:Aminolevulinic Acid; D066246:ErbB Receptors; D046988:Proteasome Endopeptidase Complex; D000077156:Gefitinib