期刊
BIOCHEMICAL PHARMACOLOGY
卷 150, 期 -, 页码 72-85出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2018.01.031
关键词
Dihydroartemisinin; ABT-263; STAT3; Mcl-1; Survivin; Bim
资金
- Natural Science Foundation of Shaanxi Province, China [2016JM8102]
- Fundamental Research Funds for the Central Universities [GK201603062, GK201603061, GK201603064]
- program of Innovative Research Team for the Central Universities [GK201701005]
- Innovation Fund for Graduate Students [2016CSY013, 2017CSY017]
- Student Innovation Training Program, Shaanxi Normal University [cx17121]
Non-small cell lung cancer (NSCLC) is the most common malignancy worldwide. A significant fraction of NSCLC carries activating mutations in epidermal growth factor receptor (EGFR) or RAS oncogene. Dihydroartemisinin (DHA) is a semisynthetic derivative of the herbal antimalarial drug artemisinin that has been recently reported to exhibit anti-cancer activity. To develop new therapeutic strategies for NSCLC, we investigated the interactions between DHA and ABT-263 in NSCLC cells harboring EGFR or RAS mutation. Our data indicated that DHA synergized with ABT-263 to trigger Bax-dependent apoptosis in NSCLC cells in culture. DHA treatment antagonized ABT-263-induced Mcl-1 upregulation and sensitized NSCLC cells to ABT-263-triggered apoptosis. Additionally, DHA treatment caused downregulation of Survivin and upregulation of Bim, which also contribute to cotreatment-induced cytotoxicity. Moreover, DHA effectively suppressed STAT3 phosphorylation, and STAT3 inactivation resulted in the downregulation of Mcl-1 and Survivin, functioning to enhance ABT-263-induced cytotoxicity. Finally, cotreatment of DHA and ABT-263 significantly inhibited xenograft growth in nude mice. Together, DHA effectively inhibits STAT3 activity and modulates expression of Mcl-1, Survivin and Bim, thereby synergizing with ABT-263 to trigger apoptosis in NSCLC cells harboring EGFR or RAS mutation. Our data provide a novel therapeutic strategy for EGFR or RAS mutant NSCLC treatment.
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