5-aminolaevulinic acid/photo-dynamic therapy and gefitinib in non-small cell lung cancer cell lines: a potential strategy to improve gefitinib therapeutic efficacy

ObjectivesOften, 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). Materials and methodsCells of the two lines were incubated with gefitinib (from 0.5 to 50mm, for 48h) then irradiated at doses ranging from 4 to 20J/cm(2); 5-ALA concentration and incubation time were kept constant (1mm for 3h). We analysed cell viability, colony-forming efficiency, cell cycle parameters, proteasome and NF-B activity and expression patterns of specific proteins, after individual or combined treatments. ResultsEffects (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-B transcriptional activity and hampered AKT pro-survival signalling. ConclusionsThe 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).