双氢青蒿素通过抑制STAT3增加非小细胞肺癌细胞对吉非替尼的敏感性  

Dihydroartemisinin enhances the sensitivity of gefitinib in non-small cell lung cancer cells by inhibiting STAT3

作　　者：蔡雪婷[1,2] 杨杰[1,2] 胡春萍[1,2] 曹鹏[1,2] CAI XueTing YANG Jie HU ChunPing CAO Peng(Laboratory of Celluar and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China Jiangsu Branch of China Academy of Chinese Medical Sciences, Nanjing 210028, China)

机构地区：[1]江苏省中医药研究院细胞与分子生物学实验室,南京210028 [2]中国中医科学院江苏分院,南京210028

出　　处：《科学通报》2017年第18期2013-2019,共7页Chinese Science Bulletin

基　　金：国家自然科学基金(81573680;81403151);江苏省自然科学基金(BK20161607)资助

摘　　要：探讨了双氢青蒿素联合吉非替尼对人非小细胞肺癌细胞(吉非替尼敏感细胞株PC-9和吉非替尼耐药细胞株H1975)的抑制效果及协同机制.运用噻唑蓝法和克隆形成实验,比较双氢青蒿素和吉非替尼单独给药和联合给药对肺癌细胞存活率和克隆形成能力的影响;利用Western blot检测单独给药和联合给药时EGFR信号通路和STAT3信号通路的变化.实验结果显示,双氢青蒿素和吉非替尼联合使用优于单独给药,联合用药指数值分别为0.751(PC-9细胞)和0.766(H1975细胞).吉非替尼诱导激活的STAT3反馈激活途径导致非小细胞肺癌对TKI产生耐药,双氢青蒿素可抑制吉非替尼激活的STAT3且不影响其TKI活性,提示双氢青蒿素可以作为解决TKI耐药的候选药物.Lung cancer is the most frequent cause of cancer death, and non-small cell lung cancer（NSCLC） is the most common subtype. EGFR（epidermal growth factor receptor） mutations are found in about 50% of Asian patients with lung adenocarcinoma and confer sensitivity to EGFR tyrosine kinase inhibitor（EGFR-TKI）. Progression free survival with TKI treatment is 9 to 12 months, and median survival time is about 20–30 months. However, acquired resistance to TKI unfailingly occurs, in most cases due to the acquisition of secondary mutations in the EGFR. Many studies have shown that bypass pathway activation（c-MET or Her-2 amplification） and the activation of the downstream pathways（PI3K/AKT, PTEN, ERK/MAPK, STAT3） can lead to acquired resistance to EGFR-TKI. In addition, transformation from NSCLC to SCLC or conferred epithelial to mesenchymal transition has also been identified as mechanisms of acquired resistance to EGFR-TKI. The need to overcome both innate and acquired resistance has been a major therapeutic challenge. Our research group aim to explore the natural compounds or their derivatives which can overcome the acquired resistance to EGFR-TKI from the library of traditional Chinese medicine monomer and related derivatives. Fortunately, we found that dihydroartemisinin（DHA） had a synergistic inhibition effect with gefitinib（first-generation EGFR-TKI） in non-small cell lung cancer cells. The combined index（CI） was 0.751 in gefitinib-sensitive cell line PC-9 cells and 0.766 in gefitinib-resistant cell line H1975 cells, respectively. DHA is a semi-synthetic derivative and main active metabolite of the artemisinin, a natural product isolated from a Chinese medicinal herb（Artemisia annua Linn.）. It is one of first-line antimalarial drugs. Moreover, DHA has been shown to exert antibacterial, antiviral and therapeutic effects on lupus erythematosus. In addition to these efficacies, evidence from epidemiological, pharmacological and case control studies has suggested that DHA possesses ant

关 键 词：双氢青蒿素 吉非替尼 非小细胞肺癌 协同效应 STAT3信号通路 

分 类 号：R285[医药卫生—中药学]