P0193Marsdenia tenacissima extract enhances gefitinib efficacy in non-small-cell lung cancer xenografts

Abstract

Listen

Translate article

Background The stem of Marsdenia tenacissima (Roxb.) Wight et Arn. has long been used as a medicine to treat cancer in China. Our previous results showed that M tenacissima extract (MTE) overcomes gefitinib resistance in NSCLC cells. Methods The present study investigated in vivo anti-tumour activity of MTE combined with gefitinib. H460 (K-RAS mutation) or H1975 cells (T790M mutation) were subcutaneously inoculated into nude mice. Tumour volume and body weight were measured during the experiment. The resected tumours were weighed after animals were sacrificed. Cellular proliferation and apoptosis in xenografts tumour tissue were assessed. EGFR downstream pathways and c-Met expression was evaluated by western blotting. In accordance with the previous in vitro study, MTE at low dose (5 g/kg) was chosen to assess whether it can restore gefitinib sensitivity in vivo. Findings MTE enhanced gefitinib efficacy in resistant H460 and H1975 xenografts. The combination significantly inhibited tumour proliferation and induced cell apoptosis in both resistant NSCLC xenografts. Constitutive activation of PI3K/Akt and MEK/ERK pathway is related to EGFR-TKI resistance. Accordingly, phosphorylation of PI3K/Akt/mTOR and ERK1/2 was suppressed after the combined treatment. Simultaneously, the cross-talk between c-Met and EGFR was also lowered in the presence of MTE combined with gefitinib. Interpretation This study provides in vivo evidence of MTE enhancing gefitinib efficacy in resistant NSCLC xenografts, and suggests that the combination of MTE and gefitinib could be a promising approach against NSCLC. The stem of Marsdenia tenacissima (Roxb.) Wight et Arn. has long been used as a medicine to treat cancer in China. Our previous results showed that M tenacissima extract (MTE) overcomes gefitinib resistance in NSCLC cells. The present study investigated in vivo anti-tumour activity of MTE combined with gefitinib. H460 (K-RAS mutation) or H1975 cells (T790M mutation) were subcutaneously inoculated into nude mice. Tumour volume and body weight were measured during the experiment. The resected tumours were weighed after animals were sacrificed. Cellular proliferation and apoptosis in xenografts tumour tissue were assessed. EGFR downstream pathways and c-Met expression was evaluated by western blotting. In accordance with the previous in vitro study, MTE at low dose (5 g/kg) was chosen to assess whether it can restore gefitinib sensitivity in vivo. MTE enhanced gefitinib efficacy in resistant H460 and H1975 xenografts. The combination significantly inhibited tumour proliferation and induced cell apoptosis in both resistant NSCLC xenografts. Constitutive activation of PI3K/Akt and MEK/ERK pathway is related to EGFR-TKI resistance. Accordingly, phosphorylation of PI3K/Akt/mTOR and ERK1/2 was suppressed after the combined treatment. Simultaneously, the cross-talk between c-Met and EGFR was also lowered in the presence of MTE combined with gefitinib. This study provides in vivo evidence of MTE enhancing gefitinib efficacy in resistant NSCLC xenografts, and suggests that the combination of MTE and gefitinib could be a promising approach against NSCLC.