APE1 overexpression is associated with cisplatin resistance in non-small cell lung cancer and targeted inhibition of APE1 enhances the activity of cisplatin in A549 cells
Received 5 October 2008; received in revised form 19 January 2009; accepted 22 February 2009. published online 26 March 2009.
Abstract
Purpose
Apurinic/apyrimidinic endonuclease (APE1), a bifunctional AP endonuclease/redox factor, is important in DNA repair and redox signaling, may be associated with chemoresistance. In this study, we first investigated APE1 expression and its correlation with cisplatin resistance and prognosis in non-small cell lung cancer (NSCLC) patients. Then, we investigated the effect of chimeric adenoviral vector Ad5/F35 carrying human APE1 siRNA (Ad5/F35-APE1 siRNA) on the sensitivity of cisplatin in A549 human lung adenocarcinoma cells.
Methods
Tumor specimens from 103 patients with operable NSCLC were obtained from 1999 to 2001. Among these patients, 72 patients have been treated with at least three cycles of cisplatin-based chemotherapy. APE1 protein expression was examined by immunohistochemistry and Western blot on the tumor samples and a cultured A549 cell line, respectively. Cell survival and apoptosis were determined by MTT and TUNEL, respectively.
Results
83.3% (20/24) cisplatin-resistant tumors showed high APE1 expression levels, while 8.3% (4/48) cisplatin-sensitive tumors showed high APE1 expression levels (p<0.01). Univariate analysis indicated that overall survival and disease-free survival were significantly better in NSCLC patients with low vs those with high APE1 expression levels (p<0.01). Treatment with cisplatin resulted in a dose-dependent increase in APE1 protein expression in A549 cells, and Ad5/F35-APE1 siRNA effectively inhibited APE1 expression. Ad5/F35-APE1 siRNA significantly enhanced sensitivity of A549 cells to cisplatin, associated with increased cell apoptosis.
Conclusions
Our results indicate that APE1 is a new promising target for the combination of cisplatin-based chemotherapy in NCSLC patients.
ABSTRACT