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Current Pharmaceutical Biotechnology

Editor-in-Chief

ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Research Article

Effects and Mechanisms of Anlotinib and Dihydroartemisinin Combination Therapy in Ameliorating Malignant Biological Behavior of Gastric Cancer Cells

Author(s): Qiong Luo, Suyun Zhang, Donghuan Zhang, Rui Feng, Nan Li, Wujin Chen*, Xiangqi Chen* and Sheng Yang*

Volume 22, Issue 4, 2021

Published on: 23 June, 2020

Page: [523 - 533] Pages: 11

DOI: 10.2174/1389201021666200623132803

Price: $65

Abstract

Background: Gastric Cancer (GC) is currently one of the major malignancies that threaten human lives and health. Anlotinib is a novel small-molecule that inhibits angiogenesis to exert antitumor effects. However, its function in gastric cancer is incompletely understood.

Objective: The aim of the present study was to investigate the anti-tumor effects and molecular mechanisms of anlotinib combined with Dihydroartemisinin (DHA) in SGC7901 gastric cancer cells.

Methods: Different concentrations of anlotinib and DHA were used to treat SGC7901 gastric cancer cells, after which cell proliferation was measured. Drug interactions of anlotinib and DHA were analyzed by the Chou-Talalay method with CompuSyn software. Proliferation, apoptosis, invasion, migration, and angiogenesis were measured using the Cell Counting Kit-8 (CCK8) assay, flow cytometry, Transwell invasion assays, scratch assays, and chicken Chorioallantoic Membrane (CAM) assays. Proliferation- associated protein (Ki67), apoptosis-related protein (Bcl-2), and Vascular Endothelial Growth Factor A (VEGF-A) were quantified by Western blotting.

Results: The combination of 2.5 μmol/L of anlotinib and 5 of μmol/L DHA was highly synergistic in inhibiting cell growth, significantly increased the apoptosis rate and suppressed obviously the invasion and migration capability and angiogenesis of gastric cancer cells. In addition, the expression levels of Ki67, Bcl-2, and VEGF-A, as well as angiogenesis, were significantly decreased in the Combination of drugs compared with control and either drug alone.

Conclusion: The combination of anlotinib and DHA showed synergistic antitumor activity, suggesting their potential in treating patients with gastric cancer.

Keywords: Anlotinib, dihydroartemisinin, gastric cancer, anti-tumor, mechanism, synergistic effect.

Graphical Abstract
[1]
Chen, W.; Zheng, R.; Baade, P.D.; Zhang, S.; Zeng, H.; Bray, F.; Jemal, A.; Yu, X.Q.; He, J. Cancer statistics in China, 2015. CA Cancer J. Clin., 2016, 66(2), 115-132.
[http://dx.doi.org/10.3322/caac.21338] [PMID: 26808342]
[2]
Sun, Y.; Niu, W.; Du, F.; Du, C.; Li, S.; Wang, J.; Li, L.; Wang, F.; Hao, Y.; Li, C.; Chi, Y. Safety, pharmacokinetics, and antitumor properties of anlotinib, an oral multi-target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors. J. Hematol. Oncol., 2016, 9(1), 105.
[http://dx.doi.org/10.1186/s13045-016-0332-8] [PMID: 27716285]
[3]
Han, B.; Li, K.; Wang, Q.; Zhang, L.; Shi, J.; Wang, Z.; Cheng, Y.; He, J.; Shi, Y.; Zhao, Y.; Yu, H.; Zhao, Y.; Chen, W.; Luo, Y.; Wu, L.; Wang, X.; Pirker, R.; Nan, K.; Jin, F.; Dong, J.; Li, B.; Sun, Y. Effect of Anlotinib as a third-line or further treatment on overall survival of patients with advanced non–small cell Lung Cancer: The ALTER 0303 Phase 3 Randomized Clinical Trial. JAMA Oncol., 2018, 4(11), 1569-1575.
[http://dx.doi.org/10.1001/jamaoncol.2018.3039] [PMID: 30098152]
[4]
Chi, Y.; Fang, Z.; Hong, X.; Yao, Y.; Sun, P.; Wang, G.; Du, F.; Sun, Y.; Wu, Q.; Qu, G.; Wang, S.; Song, J.; Yu, J.; Lu, Y.; Zhu, X.; Niu, X.; He, Z.; Wang, J.; Yu, H.; Cai, J. Safety and efficacy of anlotinib, a multikinase angiogenesis inhibitor, in patients with refractory metastatic soft-tissue sarcoma. Clin. Cancer Res., 2018, 24(21), 5233-5238.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-3766] [PMID: 29895706]
[5]
Zhang, C.Z.; Zhang, H.; Yun, J.; Chen, G.G.; Lai, P.B. Dihydroartemisinin exhibits antitumor activity toward hepatocellular carcinoma in vitro and in vivo. Biochem. Pharmacol., 2012, 83(9), 1278-1289.
[http://dx.doi.org/10.1016/j.bcp.2012.02.002] [PMID: 22342732]
[6]
Lin, R.; Zhang, Z.; Chen, L.; Zhou, Y.; Zou, P.; Feng, C.; Wang, L.; Liang, G. Dihydroartemisinin (DHA) induces ferroptosis and causes cell cycle arrest in head and neck carcinoma cells. Cancer Lett., 2016, 381(1), 165-175.
[http://dx.doi.org/10.1016/j.canlet.2016.07.033] [PMID: 27477901]
[7]
Dong, F.; Zhou, X.; Li, C.; Yan, S.; Deng, X.; Cao, Z.; Li, L.; Tang, B.; Allen, T.D.; Liu, J. Dihydroartemisinin targets VEGFR2 via the NF-κB pathway in endothelial cells to inhibit angiogenesis. Cancer Biol. Ther., 2014, 15(11), 1479-1488.
[http://dx.doi.org/10.4161/15384047.2014.955728] [PMID: 25482945]
[8]
Chou, T.C. Drug combination studies and their synergy quantification using the Chou-Talalay method., . Cancer Res., 2010, 70(2), 440-446..
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1947] [PMID: 20068163]
[9]
Guo, Q.; Liu, Y.; Zhao, J.; Wang, J.; Li, Y.; Pang, Y.; Chen, J.; Wang, J. Evodiamine inactivates NF-κB and potentiates the antitumor effects of gemcitabine on tongue cancer both in vitro and in vivo. OncoTargets Ther., 2018, 12, 257-267.
[http://dx.doi.org/10.2147/OTT.S181062] [PMID: 30643424]
[10]
Pal, P.; Hales, K.; Petrik, J.; Hales, D.B. Pro-apoptotic and anti-angiogenic actions of 2-methoxyestradiol and docosahexaenoic acid, the biologically derived active compounds from flaxseed diet, in preventing ovarian cancer. J. Ovarian Res., 2019, 12(1), 49.
[http://dx.doi.org/10.1186/s13048-019-0523-3] [PMID: 31128594]
[11]
Shen, A.L.; Hong, F.; Liu, L.Y.; Lin, J.M.; Zhuang, Q.C.; Hong, Z.F.; Peng, J. Effects of Pien Tze Huang on angiogenesis in vivo and in vitro. Chin. J. Integr. Med., 2012, 18(6), 431-436.
[http://dx.doi.org/10.1007/s11655-012-1121-z] [PMID: 22821655]
[12]
Ruan, X.; Shi, X.; Dong, Q.; Yu, Y.; Hou, X.; Song, X.; Wei, X.; Chen, L.; Gao, M. Antitumor effects of anlotinib in thyroid cancer. Endocr. Relat. Cancer, 2019, 26(1), 153-164.
[http://dx.doi.org/10.1530/ERC-17-0558] [PMID: 30139768]
[13]
Taurin, S.; Yang, C.H.; Reyes, M.; Cho, S.; Coombs, D.M.; Jarboe, E.A.; Werner, T.L.; Peterson, C.M.; Janát-Amsbury, M.M. Endometrial cancers harboring mutated fibroblast growth factor receptor 2 protein are successfully treated with a new small tyrosine kinase inhibitor in an orthotopic mouse model., Int. J. Gynecol. Cancer, 2018, 28(1), 152-160..
[http://dx.doi.org/10.1097/IGC.0000000000001129] [PMID: 28953502]
[14]
He, C.; Wu, T.; Hao, Y. Anlotinib induces hepatocellular carcinoma apoptosis and inhibits proliferation via Erk and Akt pathway. Biochem. Biophys. Res. Commun., 2018, 503(4), 3093-3099.
[http://dx.doi.org/10.1016/j.bbrc.2018.08.098] [PMID: 30146257]
[15]
Tang, L.; Yu, W.; Wang, Y.; Li, H.; Shen, Z. Anlotinib inhibits synovial sarcoma by targeting GINS1: a novel downstream target oncogene in progression of synovial sarcoma. Clin. Transl. Oncol., 2019, 21(12), 1624-1633.
[http://dx.doi.org/10.1007/s12094-019-02090-2] [PMID: 30963468]
[16]
Lu, J.; Xu, W.; Qian, J.; Wang, S.; Zhang, B.; Zhang, L.; Qiao, R.; Hu, M.; Zhao, Y.; Zhao, X.; Han, B. Transcriptome profiling analysis reveals that CXCL2 is involved in anlotinib resistance in human lung cancer cells. BMC Med. Genomics, 2019, 12(2)(Suppl. 2), 38.
[http://dx.doi.org/10.1186/s12920-019-0482-y] [PMID: 30871526]
[17]
Chen, T.; Li, M.; Zhang, R.; Wang, H. Dihydroartemisinin induces apoptosis and sensitizes human ovarian cancer cells to carboplatin therapy. J. Cell. Mol. Med., 2009, 13(7), 1358-1370..
[http://dx.doi.org/10.1111/j.1582-4934.2008.00360.x] [PMID: 18466355]
[18]
Chen, H.; Gu, S.; Dai, H.; Li, X.; Zhang, Z. Dihydroartemisinin sensitizes hμmol/Lan lung adenocarcinoma A549 cells to arsenic trioxide via apoptosis. Biol. Trace Elem. Res., 2017, 179(2), 203-212.
[http://dx.doi.org/10.1007/s12011-017-0975-5] [PMID: 28261759]
[19]
Li, N.; Zhang, S.; Luo, Q.; Yuan, F.; Feng, R.; Chen, X.; Yang, S. The Effect of Dihydroartemisinin on the Malignancy and Epithelial-Mesenchymal Transition of Gastric Cancer Cells., Curr. Pharm. Biotechnol., 2019, 20(9), 719-726. .
[http://dx.doi.org/10.2174/1389201020666190611124644] [PMID: 31187708]
[20]
Xie, C.; Wan, X.; Quan, H.; Zheng, M.; Fu, L.; Li, Y.; Lou, L. Preclinical characterization of anlotinib, a highly potent and selective vascular endothelial growth factor receptor-2 inhibitor. Cancer Sci., 2018, 109(4), 1207-1219.
[http://dx.doi.org/10.1111/cas.13536] [PMID: 29446853]
[21]
Liang, L.; Hui, K.; Hu, C.; Wen, Y.; Yang, S.; Zhu, P.; Wang, L.; Xia, Y.; Qiao, Y.; Sun, W.; Fei, J.; Chen, T.; Zhao, F.; Yang, B.; Jiang, X. Autophagy inhibition potentiates the anti-angiogenic property of multikinase inhibitor anlotinib through JAK2/STAT3/VEGFA signaling in non-small cell lung cancer cells. J. Exp. Clin. Cancer Res., 2019, 38(1), 71.
[http://dx.doi.org/10.1186/s13046-019-1093-3] [PMID: 30755242]

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