Most
gefitinib-treated patients with
non-small cell lung cancer (NSCLC) would eventually develop resistance. Lysimachia capillipes (
LC) capilliposide extracts from LC Hemsl. show both in vitro and in vivo anti-
cancer effects. In this study we investigated whether
LC capilliposide in combination with
gefitinib could overcome the resistance of NSCLC cells to
gefitinib and identified the signaling pathways involved. Treatment with
LC capilliposide alone inhibited the growth of a panel of NSCLC cell lines (PC-9, H460, H1975, H1299 and PC-9-GR) sensitive or resistant to
gefitinib with IC50 values in the range of μg/mL. In the
gefitinib-resistant PC-9-GR cells (which have a T790M EGFR mutation),
LC capilliposide (at the IC30, i.e.1.2 μg/mL) markedly enhanced the inhibitory effects of
gefitinib with its IC50 value being decreased from 6.80±1.00 to 0.77±0.12 μmol/L. By using the median effect analysis we showed that combination treatment of
LC capilliposide and
gefitinib could restore
gefitinib sensitivity in PC-9-GR cells. Furthermore,
LC capilliposide (1.2 μg/mL) significantly increased the apoptotic responses to
gefitinib (0.77 μmol/L) in PC-9-GR cells, but did not affect
gefitinib-induced G0/G1 arrest. Moreover,
LC capilliposide (1.2 μg/mL) in combination with
gefitinib (0.77, 1.0 μmol/L) markedly decreased the phosphorylation of the EGFR downstream signaling molecule AKT, which neither
LC capilliposide nor
gefitinib alone affected. In PC-9-GR cells with
siRNA knockdown of AKT, addition of
LC capilliposide was unable to increase
gefitinib sensitivity. In a PC-9-GR xenograft mouse model, combination treatment with
LC capilliposide (15 mg·kg-1·d-1, ip) and
gefitinib (50 mg·kg-1·d-1, ip) dramatically enhanced
tumor growth suppression (with a TGI of 109.3%), compared with TGIs of 22.6% and 56.6%, respectively, in mice were treated with
LC capilliposide or
gefitinib alone.
LC capilliposide can restore the cells' sensitivity to
gefitinib through modulation of pAKT levels, suggesting that a combination of
LC capilliposide and
gefitinib may be a promising therapeutic strategy to overcome
gefitinib resistance in NSCLCs with a T790M mutation.