Combination of dihydroartemisinin and gefitinib inhibits cell cycle and migration of lung adenocarcinoma cells in vitro
SONG Fanghua1, LUO Meng2, FAN Ning2, ZHOU Jiajing2,LI Yan2
1.Department of Oncology,Affiliated Xinhua Hospital of Dalian University,Dalian 116021,China; 2. Department of Human Anatomy,College of Basic Medical Science,Dalian Medical University,Dalian 116044,China
Abstract:Objective To explore the combined effect of dihydroartemisinin (DHA) and gefitinib (GEF) in lung adenocarcinoma cell lines.Methods Lung adenocarcinoma cell lines A549 and SPC-A-1 were treated with 10μM DHA and (or) 50μM GEF. MTT assay was used to detect cell proliferation, while flow cytometry was adopted to determine cell cycle. Cell migration was observed with cell scratch tests. The effects of DHA and GEF alone or in combination on the expressions of proteins related to cycle and migration were detected by Western blot.Results MTT results showed that DHA combined with GEF(Com group) inhibited the proliferation of A549 and SPC-A-1 cell lines more significantly than in control and single drug groups and in a time-dependent manner (P<0.05). Flow cytometry with PI staining showed that cell cycles were blocked at G0/G1 phase. Western blot showed that the expressions of CDK4 and Cyclin D1 in the Com group decreased more significantly than in control and single drug groups. Cell fusion rate of Com group was also significantly lower than that of control and single drug groups in cell scratch test and the expressions of MMP2 and MMP9 were decreased. The difference was statistically significant (P<0.05).Conclusions DHA combined with GEF can significantly inhibit the proliferation and migration of lung adenocarcinoma cells and block cell cycle.
宋芳华,罗蒙,范宁,周佳静,李岩. 双氢青蒿素联合吉非替尼抑制肺腺癌细胞周期和迁移能力的体外研究[J]. 武警医学, 2019, 30(3): 228-232.
SONG Fanghua, LUO Meng, FAN Ning, ZHOU Jiajing,LI Yan. Combination of dihydroartemisinin and gefitinib inhibits cell cycle and migration of lung adenocarcinoma cells in vitro. Med. J. Chin. Peop. Armed Poli. Forc., 2019, 30(3): 228-232.
Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6): 394-424.
[2]
Ernani V, Steuer C E,Jahanzeb M. The end of nihilism: systemic therapy of advanced non-small cell lung cancer[J]. Annu Rev Med, 2017, 68(1): 153-168.
[3]
Vijayvergia N,Mehra R. Clinical challenges in targeting anaplastic lymphoma kinase in advanced non-small cell lung cancer[J]. Cancer Chemother Pharmacol, 2014, 74(3): 437-446.
[4]
Giannoni E, Bianchini F, Masieri L, et al. Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-mesenchymal transition and cancer stemness[J]. Cancer Res, 2010, 70(17): 6945-6956.
[5]
Neri S, Ishii G, Hashimoto H, et al. Podoplanin-expressing cancer-associated fibroblasts lead and enhance the local invasion of cancer cells in lung adenocarcinoma[J]. Int J Cancer, 2015, 137(4): 784-796.
Cataldo V D, Gibbons D L, Perez-Soler R, et al. Treatment of non-small-cell lung cancer with erlotinib or gefitinib[J]. N Engl J Med, 2011, 364(10): 947-955.
[8]
Shi Y, Au J S, Thongprasert S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER)[J]. J Thorac Oncol, 2014, 9(2): 154-162.
[9]
Maemondo M,Inoue A,Kobayashi K,et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR[J]. N Engl J Med,2010, 362(25): 2380-2388.
[10]
Li Y, Sui H, Jiang C, et al. Dihydroartemisinin increases the sensitivity of photodynamic therapy via NF-kappaB/HIF-1alpha/VEGF pathway in esophageal cancer cell in vitro and in vivo[J]. Cell Physiol Biochem, 2018, 48(5): 2035-2045.
[11]
Chen H, Gu S, Dai H, et al. Dihydroartemisinin sensitizes human lung adenocarcinoma A549 cells to arsenic trioxide via apoptosis[J]. Biol Trace Elem Res, 2017, 179(2): 203-212.
[12]
Diluvio G, Del Gaudio F, Giuli M V, et al. NOTCH3 inactivation increases triple negative breast cancer sensitivity to gefitinib by promoting EGFR tyrosine dephosphorylation and its intracellular arrest[J]. Oncogenesis, 2018, 7(5): 42.
[13]
Peng M, Huang Y, Tao T, et al. Metformin and gefitinib cooperate to inhibit bladder cancer growth via both AMPK and EGFR pathways joining at Akt and Erk[J]. Sci Rep, 2016, 6: 28611.
Wong Y K, Xu C, Kalesh K A, et al. Artemisinin as an anticancer drug: recent advances in target profiling and mechanisms of action[J]. Med Res Rev, 2017, 37(6): 1492-1517.
[17]
Shao Y Y, Zhang T L, Wu L X, et al. AKT Axis, miR-21, and RECK play pivotal roles in dihydroartemisinin killing malignant glioma cells[J]. Int J Mol Sci, 2017, 18(2): 350.
[18]
Hu Y J, Zhang J Y, Luo Q, et al. Nanostructured dihydroartemisinin plus epirubicin liposomes enhance treatment efficacy of breast cancer by inducing autophagy and apoptosis[J]. Nanomaterials (Basel), 2018, 8(10): 804.
[19]
Gu C D, Osaki T, Oyama T, et al. Detection of micrometastatic tumor cells in pN0 lymph nodes of patients with completely resected nonsmall cell lung cancer: impact on recurrence and survival[J]. Ann Surg, 2002, 235(1): 133-139.
[20]
Martins V L, Caley M,O’Toole E A. Matrix metalloproteinases and epidermal wound repair[J]. Cell Tissue Res, 2013, 351(2): 255-268.