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 1790 M 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. (C) 2011 Elsevier Ireland Ltd. All rights reserved.