The Zinc Ionophore PCI-5002 Radiosensitizes Non-small Cell Lung Cancer Cells by Enhancing Autophagic Cell Death

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...

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Bibliographic Details
Published in:Journal of thoracic oncology 2011-09, Vol.6 (9), p.1542-1552
Main Authors: Kim, Kwang Woon, Speirs, Christina K., Jung, Dae Kwang, Lu, Bo
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Apoptosis - drug effects
Apoptosis - radiation effects
Autophagy
Autophagy - drug effects
Autophagy - radiation effects
bcl-2 Homologous Antagonist-Killer Protein - physiology
bcl-2-Associated X Protein - physiology
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Non-Small-Cell Lung - pathology
Carcinoma, Non-Small-Cell Lung - radiotherapy
Cell Line, Tumor
Cell Proliferation - drug effects
Cell Proliferation - radiation effects
Cells, Cultured
Cesium Radioisotopes
Coordination Complexes - pharmacology
Cytochromes c - metabolism
Embryo, Mammalian - cytology
Embryo, Mammalian - drug effects
Embryo, Mammalian - radiation effects
Female
Fibroblasts - drug effects
Fibroblasts - metabolism
Fibroblasts - radiation effects
Gamma Rays
Humans
Immunoblotting
Ionophores - pharmacology
Lung cancer
Lung Neoplasms - drug therapy
Lung Neoplasms - pathology
Lung Neoplasms - radiotherapy
Mice
Mice, Knockout
Mice, Nude
Radiation
Radiation-Sensitizing Agents - pharmacology
Xenograft Model Antitumor Assays
Zinc
Zinc - metabolism
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Summary: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. 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. 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 cm3 tumor size). 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.
ISSN:1556-0864
1556-1380
DOI:10.1097/JTO.0b013e3182208fac