Marsdenia tenacissima extract restored gefitinib sensitivity in resistant non-small cell lung cancer cells.

Most non-small cell lung cancer (NSCLC) patients responding to gefitinib harbor activating mutations in the epidermal growth factor receptor (EGFR). However, the responsive cases eventually develop the resistance to gefitinib. Besides, K-ras mutations were identified as the primary resistance to gefitinib. We investigated whether Marsdenia tenacissima extract (MTE, trade name: Xiao-Ai-Ping injection) combined with gefitinib could overcome the resistance of NSCLC cells to gefitinib. NSCLC cell lines with different sensitivities to gefitinib were studied. Cell growth and apoptosis were evaluated by MTT assay and flow cytometry, respectively. The EGFR-related signaling molecule phosphorylation was assessed by Western blotting. We found that MTE inhibited cell growth in gefitinib-sensitive and -resistant cells. In gefitinib-resistant cells, the MTE→MTE+gefitinib (M→M+G) treatment was most potent over the concurrent administration of MTE and gefitinib (M+G) or gefitinib→gefitinib+MTE (G→G+M) treatment in cell growth inhibition and apoptosis induction. The M→M+G treatment significantly reduced the phosphorylation of EGFR downstream signaling molecules PI3K/Akt/mTOR and ERK, on which MTE and gefitinib alone had no obvious effects on the resistant cells. The M→M+G treatment attenuated c-Met phosphorylation in H460 and H1975 as well. Thus, we found that the M→M+G treatment improved the sensitivity of resistant NSCLC cells carrying T790M or K-ras mutations to gefitinib, suggesting that the M→M+G treatment may be a promising therapeutic strategy to overcome gefitinib resistance in NSCLC.

Han SY ，Zhao MB ，Zhuang GB ，Li PP ... -  《-》

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

The stem of Marsdenia tenacissima (Roxb.) Wight et Arn. has long been used as a medicine to treat cancer in China. Our previous in vitro results showed that Marsdenia tenacissima extract (MTE) overcomes gefitinib resistance in non-small cell lung cancer (NSCLC) cells. However, it is unknown whether MTE could enhance gefitinib efficacy in vivo. The present study was intended to investigate the in vivo anti-tumour activity of MTE combined with gefitinib. Human NSCLC H460 (K-ras mutation) or H1975 cells (EGFR T790M mutation) were subcutaneously inoculated into nude mice. Tumour volume and body weight were measured regularly. Resected tumours were weighed after the animals were sacrificed. Immunoblotting or immunohistochemistry was used to assess the cellular proliferation and apoptosis in xenograft tumour tissue. Expression of the EGFR downstream pathways and c-Met were measured with western blot analysis to explore possible mechanisms. MTE (5, 10, 20 g/kg) dose-dependently reduced tumour growth and induced cell apoptosis. MTE suppressed EGFR related signals, and 20 g/kg was the most effective dose. Low-dose MTE (5 g/kg) significantly enhanced gefitinib efficacy in resistant H460 and H1975 xenografts. The combination inhibited tumour proliferation and induced cell apoptosis in both resistant NSCLC xenografts. Constitutive activation of the PI3K/Akt and MEK/ERK pathways is related to EGFR-TKI resistance. Accordingly, phosphorylation of PI3K/Akt/mTOR and ERK1/2 was suppressed after combination treatment. Simultaneously, cross-talked c-Met and EGFR were also prominently lowered in the presence of MTE combined with gefitinib. The present results suggest that the combination of MTE and gefitinib may be a promising therapeutic approach to enhance gefitinib efficacy in resistant NSCLC.

Han SY ，Zhao W ，Sun H ，Zhou N ，Zhou F ，An G ，Li PP ... -  《-》

Enhancement of gefitinib-induced growth inhibition by Marsdenia tenacissima extract in non-small cell lung cancer cells expressing wild or mutant EGFR.

Han SY ，Ding HR ，Zhao W ，Teng F ，Li PP ... -  《BMC Complementary and Alternative Medicine》

Combined inhibition of the EGFR and mTOR pathways in EGFR wild-type non-small cell lung cancer cell lines with different genetic backgrounds.

Huang Y ，Chen Y ，Mei Q ，Chen Y ，Yu S ，Xia S ... -  《-》

Knockdown of the Bcl-2 gene increases sensitivity to EGFR tyrosine kinase inhibitors in the H1975 lung cancer cell line harboring T790M mutation.

Zou M ，Xia S ，Zhuang L ，Han N ，Chu Q ，Chao T ，Peng P ，Chen Y ，Gui Q ，Yu S ... -  《-》