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Combinatorial Chemistry & High Throughput Screening

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ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

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Research Article

Apatinib Inhibits Bladder Cancer through Suppression of the VEGFR2- PI3K-AKT Signaling Pathway as Revealed by Network Pharmacology and in vitro Experimental Verification

Author(s): Weiwei Wang, Lin Chen*, Jin Yang*, Dandan Hu, Yafei Yang, Taotao Dong, Xiaoming Long, Yujian Zou, Jia Li, Xudong Ma, Wenbin Dai, Xin Zhou, Bo Chen and Yao Su

Volume 26, Issue 13, 2023

Published on: 22 March, 2023

Page: [2380 - 2392] Pages: 13

DOI: 10.2174/1386207326666230228101008

Price: $65

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Abstract

Aims: This study aimed to evaluate the underlying pharmacological mechanisms of Apatinib anti-bladder cancer via network pharmacology and experimental verification.

Methods: Network pharmacology was used to screen the possible signaling pathways of Apatinib in bladder cancer, and the most likely pathway was selected for in vitro validation. CCK-8 and colony formation assay were used to detect the effect of Apatinib on the proliferation of bladder cancer cells. Hoechst staining and flow cytometry detected apoptosis of bladder cancer cells induced by Apatinib. Western blot was performed to distinguish the effect of Apatinib on the expression levels of key targets.

Results: Apatinib can affect many signaling pathways and the correlation of the PI3K-AKT signaling pathway was the greatest. In vitro experiments showed that Apatinib could inhibit bladder cancer cell proliferation, induce apoptosis, and up-regulate the expression of apoptosisrelated proteins Cleaved-PARP and down-regulate the expression of Bcl-2. Furthermore, Apatinib could decrease the protein expression of VEGFR2, P-VEGFR2, P-PI3K and P-AKT.

Conclusions: Apatinib could promote apoptosis of bladder cancer cells by inhibiting the VEGFR2- PI3K-AKT signaling pathway.

Keywords: Apatinib, VEGFR2-PI3K-AKT, bladder cancer, network pharmacology, experimental verification, sighaling pathways.

« Previous Next »
[1]
Bray, F.; Laversanne, M.; Weiderpass, E.; Soerjomataram, I. The ever‐increasing importance of cancer as a leading cause of premature death worldwide. Cancer, 2021, 127(16), 3029-3030.
[http://dx.doi.org/10.1002/cncr.33587] [PMID: 34086348]
[2]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[3]
Wong, M.C.S.; Fung, F.D.H.; Leung, C.; Cheung, W.W.L.; Goggins, W.B.; Ng, C.F. The global epidemiology of bladder cancer: A joinpoint regression analysis of its incidence and mortality trends and projection. Sci. Rep., 2018, 8(1), 1129.
[http://dx.doi.org/10.1038/s41598-018-19199-z] [PMID: 29348548]
[4]
Lenis, A.T.; Lec, P.M.; Chamie, K.; Mshs, M. Bladder Cancer. JAMA, 2020, 324(19), 1980-1991.
[http://dx.doi.org/10.1001/jama.2020.17598] [PMID: 33201207]
[5]
Grayson, M. Bladder cancer. Nature, 2017, 551(7679), S33.
[http://dx.doi.org/10.1038/551S33a] [PMID: 29117156]
[6]
Zhang, H.; Cao, Y.; Chen, Y.; Li, G.; Yu, H. Apatinib promotes apoptosis of the SMMC-7721 hepatocellular carcinoma cell line via the PI3K/Akt pathway. Oncol. Lett., 2018, 15(4), 5739-5743.
[http://dx.doi.org/10.3892/ol.2018.8031] [PMID: 29552208]
[7]
Scott, L.J. Correction to: Apatinib: A review in advanced gastric cancer and other advanced cancers. Drugs, 2018, 78(7), 759.
[http://dx.doi.org/10.1007/s40265-018-0913-7] [PMID: 29728984]
[8]
Qin, S.; Li, Q.; Gu, S.; Chen, X.; Lin, L.; Wang, Z.; Xu, A.; Chen, X.; Zhou, C.; Ren, Z.; Yang, L.; Xu, L.; Bai, Y.; Chen, L.; Li, J.; Pan, H.; Cao, B.; Fang, W.; Wu, W.; Wang, G.; Cheng, Y.; Yu, Z.; Zhu, X.; Jiang, D.; Lu, Y.; Wang, H.; Xu, J.; Bai, L.; Liu, Y.; Lin, H.; Wu, C.; Zhang, Y.; Yan, P.; Jin, C.; Zou, J. Apatinib as second-line or later therapy in patients with advanced hepatocellular carcinoma (AHELP): A multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol. Hepatol., 2021, 6(7), 559-568.
[http://dx.doi.org/10.1016/S2468-1253(21)00109-6] [PMID: 33971141]
[9]
Li, S.; Zhang, B. Traditional Chinese medicine network pharmacology: Theory, methodology and application. Chin. J. Nat. Med., 2013, 11(2), 110-120.
[http://dx.doi.org/10.1016/S1875-5364(13)60037-0] [PMID: 23787177]
[10]
Nogales, C.; Mamdouh, Z.M.; List, M.; Kiel, C.; Casas, A.I.; Schmidt, H.H.H.W. Network pharmacology: Curing causal mechanisms instead of treating symptoms. Trends Pharmacol. Sci., 2022, 43(2), 136-150.
[http://dx.doi.org/10.1016/j.tips.2021.11.004] [PMID: 34895945]
[11]
Neto, R.A.M.; Santos, C.B.R.; Henriques, S.V.C.; Machado, L.O.; Cruz, J.N.; da Silva, C.H.T.P.; Federico, L.B.; Oliveira, E.H.C.; de Souza, M.P.C.; da Silva, P.N.B.; Taft, C.A.; Ferreira, I.M.; Gomes, M.R.F. Novel chalcones derivatives with potential antineoplastic activity investigated by docking and molecular dynamics simulations. J. Biomol. Struct. Dyn., 2022, 40(5), 2204-2216.
[http://dx.doi.org/10.1080/07391102.2020.1839562] [PMID: 33146078]
[12]
da Silva Júnior, O.S.; Franco, C.J.P.; de Moraes, A.A.B.; Cruz, J.N.; da Costa, K.S.; do Nascimento, L.D.; Andrade, E.H.A. In silico analyses of toxicity of the major constituents of essential oils from two Ipomoea L. species. Toxicon, 2021, 195, 111-118.
[http://dx.doi.org/10.1016/j.toxicon.2021.02.015] [PMID: 33667485]
[13]
Liang, B.; Gao, L.; Wang, F.; Li, Z.; Li, Y.; Tan, S.; Chen, A.; Shao, J.; Zhang, Z.; Sun, L.; Zhang, F.; Zheng, S. The mechanism research on the anti‐liver fibrosis of emodin based on network pharmacology. IUBMB Life, 2021, 73(9), 1166-1179.
[http://dx.doi.org/10.1002/iub.2523] [PMID: 34173707]
[14]
Peng, H.; Zhang, Q.; Li, J.; Zhang, N.; Hua, Y.; Xu, L.; Deng, Y.; Lai, J.; Peng, Z.; Peng, B.; Chen, M.; Peng, S.; Kuang, M. Apatinib inhibits VEGF signaling and promotes apoptosis in intrahepatic cholangiocarcinoma. Oncotarget, 2016, 7(13), 17220-17229.
[http://dx.doi.org/10.18632/oncotarget.7948] [PMID: 26967384]
[15]
Liao, J.; Jin, H.; Li, S.; Xu, L.; Peng, Z.; Wei, G.; Long, J.; Guo, Y.; Kuang, M.; Zhou, Q.; Peng, S. Apatinib potentiates irradiation effect via suppressing PI3K/AKT signaling pathway in hepatocellular carcinoma. J. Exp. Clin. Cancer Res., 2019, 38(1), 454.
[http://dx.doi.org/10.1186/s13046-019-1419-1] [PMID: 31694662]
[16]
Daina, A.; Michielin, O.; Zoete, V. SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res., 2019, 47(W1), W357-W364.
[http://dx.doi.org/10.1093/nar/gkz382] [PMID: 31106366]
[17]
Shannon, P.; Markiel, A.; Ozier, O.; Baliga, N.S.; Wang, J.T.; Ramage, D.; Amin, N.; Schwikowski, B.; Ideker, T. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res., 2003, 13(11), 2498-2504.
[http://dx.doi.org/10.1101/gr.1239303] [PMID: 14597658]
[18]
Huang, D.W.; Sherman, B.T.; Lempicki, R.A. Bioinformatics enrichment tools: Paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res., 2009, 37(1), 1-13.
[http://dx.doi.org/10.1093/nar/gkn923] [PMID: 19033363]
[19]
Huang, D.W.; Sherman, B.T.; Lempicki, R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc., 2009, 4(1), 44-57.
[http://dx.doi.org/10.1038/nprot.2008.211] [PMID: 19131956]
[20]
Carneiro, B.A.; El-Deiry, W.S. Targeting apoptosis in cancer therapy. Nat. Rev. Clin. Oncol., 2020, 17(7), 395-417.
[http://dx.doi.org/10.1038/s41571-020-0341-y] [PMID: 32203277]
[21]
Li, J.; Ma, W.; Cheng, X.; Zhang, X.; Xie, Y.; Ji, Z.; Wu, S. Activation of FOXO3 pathway is involved in polyphyllin I-induced apoptosis and cell cycle arrest in human bladder cancer cells. Arch. Biochem. Biophys., 2020, 687, 108363.
[http://dx.doi.org/10.1016/j.abb.2020.108363] [PMID: 32335049]
[22]
Long, X.; Chen, L.; Yang, J.; Dong, T.; Cheng, Q.; Wang, W.; Zou, Y.; Su, Y.; Dai, W.; Chen, B.; Zhou, X. Network-based pharmacology and in vitro validation reveal that galangin induces apoptosis in bladder cancer cells by promoting the p53 signaling pathway. Anticancer. Agents Med. Chem., 2022, 23.
[http://dx.doi.org/10.2174/1871520623666221026121600] [PMID: 36305128]
[23]
Scott, L.J. Apatinib: A review in advanced gastric cancer and other advanced cancers. Drugs, 2018, 78(7), 747-758.
[http://dx.doi.org/10.1007/s40265-018-0903-9] [PMID: 29663291]
[24]
Xie, C.; Zhou, X.; Liang, C.; Li, X.; Ge, M.; Chen, Y.; Yin, J.; Zhu, J.; Zhong, C. Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer. J. Exp. Clin. Cancer Res., 2021, 40(1), 266.
[http://dx.doi.org/10.1186/s13046-021-02069-4] [PMID: 34429133]
[25]
Geng, R.; Song, L.; Li, J.; Zhao, L. The safety of apatinib for the treatment of gastric cancer. Expert Opin. Drug Saf., 2018, 17(11), 1145-1150.
[http://dx.doi.org/10.1080/14740338.2018.1535592] [PMID: 30324820]
[26]
Du, Z.; Lovly, C.M. Mechanisms of receptor tyrosine kinase activation in cancer. Mol. Cancer, 2018, 17(1), 58.
[http://dx.doi.org/10.1186/s12943-018-0782-4] [PMID: 29455648]
[27]
Hallberg, B.; Palmer, R.H. Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology. Nat. Rev. Cancer, 2013, 13(10), 685-700.
[http://dx.doi.org/10.1038/nrc3580] [PMID: 24060861]
[28]
Claesson-Welsh, L.; Welsh, M. VEGFA and tumour angiogenesis. J. Intern. Med., 2013, 273(2), 114-127.
[http://dx.doi.org/10.1111/joim.12019] [PMID: 23216836]
[29]
Song, F.; Hu, B.; Cheng, J.W.; Sun, Y.F.; Zhou, K.Q.; Wang, P.X.; Guo, W.; Zhou, J.; Fan, J.; Chen, Z.; Yang, X.R. Anlotinib suppresses tumor progression via blocking the VEGFR2/PI3K/AKT cascade in intrahepatic cholangiocarcinoma. Cell Death Dis., 2020, 11(7), 573.
[http://dx.doi.org/10.1038/s41419-020-02749-7] [PMID: 32709873]
[30]
Liu, K.; Ren, T.; Huang, Y.; Sun, K.; Bao, X.; Wang, S.; Zheng, B.; Guo, W. Apatinib promotes autophagy and apoptosis through VEGFR2/STAT3/BCL-2 signaling in osteosarcoma. Cell Death Dis., 2017, 8(8), e3015.
[http://dx.doi.org/10.1038/cddis.2017.422] [PMID: 28837148]
[31]
Xu, F.; Na, L.; Li, Y.; Chen, L. RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours. Cell Biosci., 2020, 10(1), 54.
[http://dx.doi.org/10.1186/s13578-020-00416-0] [PMID: 32266056]
[32]
Wang, Y.; Chu, F.; Lin, J.; Li, Y.; Johnson, N.; Zhang, J.; Gai, C.; Su, Z.; Cheng, H.; Wang, L.; Ding, X. Erianin, the main active ingredient of Dendrobium chrysotoxum Lindl, inhibits precancerous lesions of gastric cancer (PLGC) through suppression of the HRAS-PI3K-AKT signaling pathway as revealed by network pharmacology and in vitro experimental verification. J. Ethnopharmacol., 2021, 279, 114399.
[http://dx.doi.org/10.1016/j.jep.2021.114399] [PMID: 34246740]
[33]
Mao, W.P.; Ye, J.L.; Guan, Z.B.; Zhao, J.M.; Zhang, C.; Zhang, N.N.; Jiang, P.; Tian, T. Cadmium induces apoptosis in human embryonic kidney (HEK) 293 cells by caspase-dependent and -independent pathways acting on mitochondria. Toxicol. In Vitro, 2007, 21(3), 343-354.
[http://dx.doi.org/10.1016/j.tiv.2006.09.004] [PMID: 17052885]
[34]
Zheng, L.; Zheng, J.; Wu, L.J.; Zhao, Y.Y. Julibroside J8-induced HeLa cell apoptosis through caspase pathway. J. Asian Nat. Prod. Res., 2006, 8(5), 457-465.
[http://dx.doi.org/10.1080/10286020500173309] [PMID: 16864463]

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