title: The impact of autophagy on cell death modalities in CRL-5876 lung adenocarcinoma cells after their exposure to γ-rays and/or erlotinib.
abstract: In most patients with lung cancer radiation treatment is used either as single agent or in combination with radiosensitizing drugs. However, the mechanisms underlying combined therapy and its impact on different modes of cell death have not yet been fully elucidated. We aimed to examine effects of single and combined treatments with γ-rays and erlotinib on radioresistant CRL-5876 human lung adenocarcinoma cells with particular emphasis on cell death. CRL-5876 cells were treated with γ-rays and/or erlotinib and changes in cell cycle, DNA repair dynamics, ultrastructure, nuclear morphology and protein expression were monitored at different time points. To reveal the relationship between types of cell death that arise after these treatments, autophagy was blocked with chloroquine. We found that higher dose of γ-rays causes G2/M arrest while adding of erlotinib to this treatment decreases the number of cells in S phase. Impact of erlotinib on kinetics of disappearance of irradiation-induced DNA double strand breaks is reflected in the increase of residual γ-H2AX foci after 24 h. γ-rays provoke cytoprotective autophagy which precedes development of senescence. Erlotinib predominantly induces apoptosis and enlarges the number of apoptotic cells in the irradiated CRL-5876 cells. Chloroquine improved cytotoxicity induced by radiation and erlotinib, increased apoptosis and decreased senescence in the CRL-5876 cells. The results obtained on CRL-5876 cells indicate significant radiosensitizing effect of erlotinib and suggest that chloroquine in the combination with the above treatments may have an additional antitumor effect in lung adenocarcinoma.
authors.affiliation: Vinča Institute of Nuclear Sciences, University of Belgrade, PO Box 522, 11001, Belgrade, Serbia.
authors.forename: Otilija
authors.initials: O
authors.lastname: Keta
authors.affiliation: Vinča Institute of Nuclear Sciences, University of Belgrade, PO Box 522, 11001, Belgrade, Serbia.
authors.forename: Tanja
authors.initials: T
authors.lastname: Bulat
authors.affiliation: Faculty of Biology, University of Belgrade, Belgrade, Serbia.
authors.forename: Igor
authors.initials: I
authors.lastname: Golić
authors.affiliation: CNRS/IN2P3, Centre d'Etudes Nucléaires de Bordeaux Gradignan, CENBG, Université Bordeaux 1, 33175, Gradignan, France.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Incerti
authors.affiliation: Faculty of Biology, University of Belgrade, Belgrade, Serbia.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Korać
authors.affiliation: Vinča Institute of Nuclear Sciences, University of Belgrade, PO Box 522, 11001, Belgrade, Serbia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Petrović
authors.affiliation: Vinča Institute of Nuclear Sciences, University of Belgrade, PO Box 522, 11001, Belgrade, Serbia. aristic@vin.bg.ac.rs.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Ristić-Fira
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001343:Autophagy / Q000187:drug effects / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D005720:Gamma Rays / Q000627:therapeutic use*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*
chemical_list: D000970:Antineoplastic Agents; D002738:Chloroquine; D000069347:Erlotinib Hydrochloride
keywords: Apoptosis; Autophagy; Erlotinib; Lung adenocarcinoma; Senescence; γ-rays