Combination of S-1 and gefitinib increases the sensitivity to radiotherapy in lung cancer cells.

Abstract

To investigate the potential radiosensitization of S-1 and gefitinib in human non-small cell lung cancer (NSCLC) in vitro and in vivo. The impact of radiation, 5-fluorouracil (5-Fu), and gefitinib on the proliferation and apoptosis of human NSCLC A549, H1299, H1975, and HCC827 cells was examined by MTT and flow cytometry. The effect of radiation, 5-Fu, and gefitinib on the clonogenicity of H1975 and HCC827 cells was determined by colony formation assay. The effect of radiation, 5-fluorouracil (5-Fu), and gefitinib on the EGFR, AKT, and ERK1/2 activation in H1975 cells was determined by Western blot. The therapeutic efficacy of radiation, S-1, and gefitinib in the growth of implanted H1975 tumors and the AKT activation in the tumors were examined in vivo and immunohistochemistry, respectively. Combination of radiation, 5-Fu, and gefitinib significantly inhibited the proliferation of H1975 cells and triggered their apoptosis, but not other NSCLC cells tested. The combination therapy significantly mitigated the clonogenicity and attenuated the activation of EGFR and AKT signaling in H1975 cells. Furthermore, combination of S-1, gefitinib, and radiation significantly inhibited the growth of implanted H1975 tumors in mice and remarkably reduced the AKT phosphorylation in the tumors. Our data indicated that combination of S-1 and gefitinib significantly increased radiosensitivity of H1975 cells. The triple combination therapies may benefit patients with the EGFR T790M mutant NSCLC.