TY - JOUR
T1 - The zinc ionophore PCI-5002 radiosensitizes non-small cell lung cancer cells by enhancing autophagic cell death
AU - Kim, Kwang Woon
AU - Speirs, Christina K.
AU - Jung, Dae Kwang
AU - Lu, Bo
PY - 2011/9
Y1 - 2011/9
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Autophagy
KW - Lung cancer
KW - Radiation
KW - Zinc
UR - http://www.scopus.com/inward/record.url?scp=80052273362&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80052273362&partnerID=8YFLogxK
U2 - 10.1097/JTO.0b013e3182208fac
DO - 10.1097/JTO.0b013e3182208fac
M3 - Article
C2 - 21642866
AN - SCOPUS:80052273362
SN - 1556-0864
VL - 6
SP - 1542
EP - 1552
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 9
ER -