Dihydroartemisinin and gefitinib synergistically inhibit NSCLC cell growth and promote apoptosis via the Akt/mTOR/STAT3 pathway

被引:45
作者
Jin, Hong [1 ]
Jiang, Ai-Ying [2 ]
Wang, Han [3 ]
Cao, Yong [4 ]
Wu, Yan [5 ]
Jiang, Xiao-Feng [1 ]
机构
[1] Harbin Med Univ, Affiliated Hosp 4, Dept Clin Lab, 37 Yiyuan St, Harbin 150001, Heilongjiang, Peoples R China
[2] Mudanjiang Med Univ, Dept Pneumol, Hongqi Hosp, Mudanjiang 157011, Heilongjiang, Peoples R China
[3] Mudanjiang Med Univ, Dept Clin Skills Ctr, Mudanjiang 157011, Heilongjiang, Peoples R China
[4] Mudanjiang Med Univ, Dept Pathol, Mudanjiang 157011, Heilongjiang, Peoples R China
[5] Mudanjiang Med Univ, Dept Med Res Ctr, Mudanjiang 157011, Heilongjiang, Peoples R China
关键词
non-small cell lung cancer; dihydroartemisinin; gefitinib; Akt; mTOR; STAT3; NATURAL-PRODUCTS; CANCER CELLS; CYCLE ARREST; LUNG-CANCER; IN-VITRO; ADJUVANT CHEMOTHERAPY; ANTICANCER ACTIVITY; BCL-2; PROTEIN; STAGE-II; BAX;
D O I
10.3892/mmr.2017.6989
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Non-small cell lung cancer (NSCLC) is among the leading causes of cancer-associated mortality worldwide. In clinical practice, therapeutic strategies based on drug combinations are often used for the treatment of various types of cancer. The present study aimed to investigate the effects of the combination of dihydroartemisinin (DHA) and gefitinib on NSCLC. Cell Counting kit 8 assay was used to evaluate cell viability. Transwell assays were performed to investigate cellular migration and invasion, and cellular apoptosis was evaluated using the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Flow cytometry was used to investigate cell cycle distribution and the expression levels of target proteins were determined using western blot analysis. The results of the present study demonstrated that DHA (5, 10, 20, 50 and 100 mu M) reduced cancer cell viability in a dose-dependent manner in the NCI-H1975 human NSCLC cell line and significantly enhanced gefitinib-induced apoptosis. Furthermore, DHA and gefitinib co-administration induced cell cycle arrest in G(2)/M phase, which was associated with a marked decline in the protein expression levels of G(2)/M regulatory proteins, including cyclin B1 and cyclin-dependent kinase 1. The addition of DHA appeared to potentiate the inhibitory actions of gefitinib on the migratory and invasive capabilities of NCI-H1975 cells. DHA and gefitinib co-administration also downregulated the expression levels of phosphorylated (p)-Akt, p-mechanistic target of rapamycin, p-signal transducer and activator of transcription 3 and B-cell lymphoma 2 (Bcl-2), and upregulated the expression of Bcl-2-associated X protein. In conclusion, the present results suggested that the combination of DHA and gefitinib may have potential as a novel and more effective therapeutic strategy for the treatment of patients with NSCLC.
引用
收藏
页码:3475 / 3481
页数:7
相关论文
共 44 条
[1]   The Bcl-2 protein family: Arbiters of cell survival [J].
Adams, JM ;
Cory, S .
SCIENCE, 1998, 281 (5381) :1322-1326
[2]  
ALBERTI W, 1995, BRIT MED J, V311, P899
[3]   Anticancer drugs from nature - natural products as a unique source of new microtubule-stabilizing agents [J].
Altmann, Karl-Heinz ;
Gertsch, Juerg .
NATURAL PRODUCT REPORTS, 2007, 24 (02) :327-357
[4]  
Brambilla E, 1996, AM J PATHOL, V149, P1941
[5]   Chemotherapy, chemoresistance and the changing treatment landscape for NSCLC [J].
Chang, Alex .
LUNG CANCER, 2011, 71 (01) :3-10
[6]   Curcumin induces apoptosis in human breast cancer cells through p53-dependent Bax induction [J].
Choudhuri, T ;
Pal, S ;
Agwarwal, ML ;
Das, T ;
Sa, G .
FEBS LETTERS, 2002, 512 (1-3) :334-340
[7]   United States Food and Drug Administration drug approval summary: Gefitinib (ZD1839; Iressa) tablets [J].
Cohen, MH ;
Williams, GA ;
Sridhara, R ;
Chen, G ;
McGuinn, WD ;
Morse, D ;
Abraham, S ;
Rahman, A ;
Liang, CY ;
Lostritto, R ;
Baird, A ;
Pazdur, R .
CLINICAL CANCER RESEARCH, 2004, 10 (04) :1212-1218
[8]   mTOR in aging, metabolism, and cancer [J].
Cornu, Marion ;
Albert, Verena ;
Hall, Michael N. .
CURRENT OPINION IN GENETICS & DEVELOPMENT, 2013, 23 (01) :53-62
[9]   Quercetin attenuates doxorubicin cardiotoxicity by modulating Bmi-1 expression [J].
Dong, Qinghua ;
Chen, Long ;
Lu, Qunwei ;
Sharma, Sherven ;
Li, Lei ;
Morimoto, Sachio ;
Wang, Guanyu .
BRITISH JOURNAL OF PHARMACOLOGY, 2014, 171 (19) :4440-4454
[10]   Arsenic Trioxide and Resveratrol Show Synergistic Anti-Leukemia Activity and Neutralized Cardiotoxicity [J].
Fan, Yuhua ;
Chen, Meng ;
Meng, Jia ;
Yu, Lei ;
Tu, Yingfeng ;
Wan, Lin ;
Fang, Kun ;
Zhu, Wenliang .
PLOS ONE, 2014, 9 (08)