title: The zinc ionophore PCI-5002 radiosensitizes non-small cell lung cancer cells by enhancing autophagic cell death.
abstract: BACKGROUND
  A major focus of cancer research is to identify compounds that sensitize resistant cancer cells to radiation treatment. Lung cancer cells, in particular, have high rates of radioresistance that lead to treatment failure. We have previously shown that the autophagy induced in the context of decreased apoptosis confers radiosensitivity to prostate and lung cancer cells. Zinc supplementation has antiapoptotic effects in cell culture. In addition, the accumulation of zinc in response to oxidative stress has been associated with increased autophagy in astrocyte and breast cancer cells.
  
  
  METHODS
  In this study, we hypothesized that the zinc ionophore PCI-5002 radiosensitizes lung cancer cells by inducing autophagic cell death. To test this hypothesis, we used a combination of in vitro and in vivo approaches, including clonogenic assays to test for radiosensitivity, biochemical analyses of apoptosis and autophagy, and a xenograft mouse model of tumor growth.
  
  
  RESULTS
  We found that PCI-5002 reduced clonogenic survival in treated cells compared with untreated cells (0.03% versus 0.1% surviving fraction, p < 0.001). The increased radiosensitive fraction of PCI-5002-treated cells was accompanied by increased autophagy. PCI-5002 treatment also reduced caspase-3 cleavage. In an irradiated xenograft mouse model, the tumor growth of irradiated, PCI-5002-treated mice was slower than untreated, irradiated mice (25 days versus 22 days to reach a 1.0 cm tumor size).
  
  
  CONCLUSIONS
  PCI-5002 treatment sensitizes lung cancer cells to radiation, both in vitro and in vivo. This data suggest that PCI-5002 could potentially treat radioresistant/locally advanced lung cancer by amplifying the effects of radiotherapy.
authors.affiliation: Department of Radiation Oncology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232-5671, USA.
authors.forename: Kwang Woon
authors.initials: KW
authors.lastname: Kim
authors.forename: Christina K
authors.initials: CK
authors.lastname: Speirs
authors.forename: Dae Kwang
authors.initials: DK
authors.lastname: Jung
authors.forename: Bo
authors.initials: B
authors.lastname: Lu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001343:Autophagy / Q000187:drug effects* / Q000528:radiation effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D002588:Cesium Radioisotopes; D056831:Coordination Complexes / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D005720:Gamma Rays; D006801:Humans; D015151:Immunoblotting; D007476:Ionophores / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D015032:Zinc / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000502:physiology
chemical_list: C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D002588:Cesium Radioisotopes; D056831:Coordination Complexes; D007476:Ionophores; C568608:PCI 5002; D011838:Radiation-Sensitizing Agents; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D015032:Zinc