The zinc ionophore PCI-5002 radiosensitizes non-small cell lung cancer cells by enhancing autophagic cell death

Kwang Woon Kim, Christina K. Speirs, Dae Kwang Jung, Bo Lu

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1542-1552
Number of pages11
JournalJournal of Thoracic Oncology
Volume6
Issue number9
DOIs
StatePublished - Sep 2011
Externally publishedYes

Keywords

  • Apoptosis
  • Autophagy
  • Lung cancer
  • Radiation
  • Zinc

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Fingerprint Dive into the research topics of 'The zinc ionophore PCI-5002 radiosensitizes non-small cell lung cancer cells by enhancing autophagic cell death'. Together they form a unique fingerprint.

  • Cite this