消癌平注射液提高吉非替尼在耐药非小细胞肺癌荷瘤裸鼠的疗效研究

he 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 Marsdenia tenacissima extract (MTE) overcomes gefitinib resistance in NSCLC cells. The present study investigated in vivo anti-tumor activity of MTE combined with gefitinib. H460 (K-ras mutation) or H1975 cells (T790M mutation) was subcutaneously inoculated into nude mice. Tumor volume and body weight were measured during the experiment. The resected tumors were weighed after animals were sacrificed. Cellular proliferation and apoptosis in xenografts tumor 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. Interestingly, MTE prominently enhanced gefitinib efficacy in the resistant H460 and H1975 xenografts. This combination significantly inhibited tumor 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-talked c-Met and EGFR was also prominently lowered in the presence of MTE combined with gefitinib. This study provides in vivo evidence to demonstrate that MTE enhancing gefitinib efficacy in the resistant NSCLC xenografts, and suggests the combination of MTE and gefitinib as a promising approach against NSCLC.