中草藥: NTU03抗非小細胞肺癌之研究

Abstract

Lung cancer is the leading cause of cancer deaths in Taiwan and worldwide, and the two major forms of lung cancer are non–small-cell lung cancer (NSCLC) (about 85% of all lung cancers) and small-cell lung cancer (about 15%). NSCLC is often diagnosed at an advanced stage and has a poor prognosis. It is frequently overexpressed and mutated (Ex: in-frame deletion △E746-A750 on exon 19, and L858R mutation on exon 20) in the Epidermal growth factor receptor (EGFR) during the development and progression of NSCLC. Recently, tyrosine kinase inhibitors (TKIs) have been used to treat selected NSCLC patients with EGFR mutations, but the long-term efficacy of such treatments is generally limited due to the development of resistance. Therefore, to develop novel therapeutic agents or strategies for the treatment of TKI-resistant tumors is urgently needed. In this study, we set up a platform to screen extracts of CHMs on the inhibitory effects on the growth of H1975 cell line, which harbors EGFR T790M/L858R mutations and is resistant to TKIs, such as gefitinib. We found that the water extracts from NTU03 inhibited cell growth and proliferation of H1975 cells through Raf/Ras/Erk pathway. The extract also inhibited cell migration through FAK/Src signaling pathway and reduced RhoA activity, which led to inhibition of actin filament rearrangement and reduction of migration ability. In addition, extracts from NTU03 could attenuate Akt/Bcl2 signaling, promote Caspase-9/-3 and PARP cleavage, which then induced apoptosis. Besides, the level of VEGFA expression was reduced and the tube formation ability of human vascular endothelial cells was also suppressed. We further showed that NTU03 also had an inhibitory effect on tumor growth in vivo by a mouse xenograft model. By drug combination assay, we also found synergistic inhibitory effects of NTU03 combined with gefitinib on H1975 cell growth. Taken together, NTU03 may be a potential therapeutic agent for NSCLC treatment.