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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

Network-based Pharmacology and In vitro Validation Reveal that Galangin Induces Apoptosis in Bladder Cancer Cells by Promoting the P53 Signaling Pathway

Author(s): Xiaoming Long, Lin Chen*, Jin Yang*, Taotao Dong, Qisen Cheng, Weiwei Wang, Yujian Zou, Yao Su, Wenbin Dai, Bo Chen and Xin Zhou

Volume 23, Issue 7, 2023

Published on: 10 November, 2022

Page: [847 - 857] Pages: 11

DOI: 10.2174/1871520623666221026121600

Price: $65

Abstract

Background: Galangin is one of the flavonoids in Alpinia officinarum. It has various anti-tumor activities, but its anti-bladder cancer effect is unclear.

Objective: To investigate the mechanism of action of galangin against bladder cancer using a network pharmacology approach.

Methods: The TCM Systematic Pharmacology Database and Analysis Platform (TCMSP), SwissTargetPrediction database, and the Targetnet database were used to predict the targets of action of galangin. Bladder cancer-related targets were obtained through the GeneCards database. The intersection of the two was taken as the target of galangin's action against bladder cancer. The intersecting targets were screened for core targets using the STRING database and Cytoscape 3.9.0 software to build a protein-protein interaction (PPI) network of targets. The core targets were subjected to gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis using the online annotation and visual integration analysis tool DAVIDBioinformaticsResources (2021Update). A drug-disease-target-pathway network was constructed using Cytoscape 3.9.0 software. The antibladder cancer effect of galangin was observed by cell proliferation, and plate cloning assay; apoptosis of bladder cancer cells induced by galangin was detected by Hoechst33342 staining and flow cytometry; protein immunoblotting (Western-blot) was used to detect the effect of galangin on apoptosis-related proteins Bax, Bcl-2, Cleaved-PARP, p53 signaling pathway p53 and cytc.

Results: A total of 115 genes were obtained from galangin against bladder cancer, and 16 core targets were screened. The kEGG pathway enrichment analysis included Pathways in cancer, PI3K-AKT signaling pathway, p53 signaling pathway, etc. In vitro experiments showed that galangin could inhibit bladder cancer cell proliferation, induce apoptosis, upregulate the expression of apoptosis-related proteins Bax and Cleaved-PARP and downregulate the expression of Bcl-2; meanwhile, galangin could promote the upregulation of the expression of p53 and cytc proteins by activating the p53 signaling pathway.

Conclusion: Galangin induced apoptosis in bladder cancer cells by activating the p53 signaling pathway.

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[1]
Rozanec, J.J.; Secin, F.P. Epidemiology, etiology and prevention of bladder cancer. Arch. Esp. Urol., 2020, 73(10), 872-878.
[PMID: 33269706]
[2]
Antoni, S.; Ferlay, J.; Soerjomataram, I.; Znaor, A.; Jemal, A.; Bray, F. Bladder cancer incidence and mortality: A global overview and recent trends. Eur. Urol., 2017, 71(1), 96-108.
[http://dx.doi.org/10.1016/j.eururo.2016.06.010] [PMID: 27370177]
[3]
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]
[4]
Li, H.; Rongshou, Z.; Lingbin, D.; Sixian, Z.; Chen, Z.; Wenqiang, W.; Jie, H. Analysis of epidemic status and trend of bladder cancer in China. 2021, 43(3), 293-298.
[5]
Xia, C.; Dong, X.; Li, H.; Cao, M.; Sun, D.; He, S.; Yang, F.; Yan, X.; Zhang, S.; Li, N.; Chen, W. Cancer statistics in China and United States, 2022: Profiles, trends, and determinants. Chin. Med. J. (Engl.), 2022, 135(5), 584-590.
[http://dx.doi.org/10.1097/CM9.0000000000002108] [PMID: 35143424]
[6]
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]
[7]
Chou, R.; Selph, S.S.; Buckley, D.I.; Gustafson, K.S.; Griffin, J.C.; Grusing, S.E.; Gore, J.L. Treatment of muscle-invasive bladder cancer: A systematic review. Cancer, 2016, 122(6), 842-851.
[http://dx.doi.org/10.1002/cncr.29843] [PMID: 26773572]
[8]
Ghandour, R.; Singla, N.; Lotan, Y. Treatment options and outcomes in nonmetastatic muscle invasive bladder cancer. Trends Cancer, 2019, 5(7), 426-439.
[http://dx.doi.org/10.1016/j.trecan.2019.05.011] [PMID: 31311657]
[9]
Zhang, J.J.; Cai, L.J.; Pang, K.; Dong, Y.; Zhang, Z.G.; Li, B.B.; Li, R.; Han, C.H. Paeonol inhibits proliferation and induces cell apoptosis of human T24 and 5637 bladder cancer cells in vitro and in vivo. Clin. Transl. Oncol., 2021, 23(3), 601-611.
[http://dx.doi.org/10.1007/s12094-020-02455-y] [PMID: 32691366]
[10]
Zhao, F.; Vakhrusheva, O.; Markowitsch, S.D.; Slade, K.S.; Tsaur, I.; Cinatl, J., Jr; Michaelis, M.; Efferth, T.; Haferkamp, A.; Juengel, E. Artesunate impairs growth in cisplatin-resistant bladder cancer cells by cell cycle arrest, apoptosis and autophagy induction. Cells, 2020, 9(12), 2643.
[http://dx.doi.org/10.3390/cells9122643] [PMID: 33316936]
[11]
Jo, G.; Kwon, M.J.; Kim, J.N.; Kim, B.J. Radix sophorae flavescentis induces apoptosis through by caspase, mapk activation and ros signaling pathways in 5637 human bladder cancer cells. Int. J. Med. Sci., 2020, 17(11), 1474-1481.
[http://dx.doi.org/10.7150/ijms.45831] [PMID: 32669949]
[12]
Yu, S.; Gong, L.; Li, N.; Pan, Y.; Zhang, L. Galangin (GG) combined with cisplatin (DDP) to suppress human lung cancer by inhibition of STAT3-regulated NF-κB and Bcl-2/Bax signaling pathways. Biomed. Pharmacother., 2018, 97, 213-224.
[http://dx.doi.org/10.1016/j.biopha.2017.10.059] [PMID: 29091869]
[13]
Abubakar, I.B.; Malami, I.; Yahaya, Y.; Sule, S.M. A review on the ethnomedicinal uses, phytochemistry and pharmacology of Alpinia officinarum Hance. J. Ethnopharmacol., 2018, 224, 45-62.
[http://dx.doi.org/10.1016/j.jep.2018.05.027] [PMID: 29803568]
[14]
Yang, D.A. Inhibitory effect of Chinese herb medicine zhuling on urinary bladder cancer. An experimental and clinical study. Zhonghua Wai Ke Za Zhi, 1991, 29(6), 393-395, 399. [Inhibitory effect of Chinese herb medicine zhuling on urinary bladder cancer. An experimental and clinical study]
[PMID: 1935440]
[15]
Ebisuno, S.; Hirano, A.; Kyoku, I.; Ohkawa, T.; Iijima, O.; Fujii, Y.; Hosoya, E. Basal studies on combination of Chinese medicine in cancer chemotherapy: Protective effects on the toxic side effects of CDDP and antitumor effects with CDDP on murine bladder tumor (MBT-2). Nihon Gan Chiryo Gakkai Shi, 1989, 24(6), 1305-1312.
[PMID: 2794654]
[16]
Cushnie, T.P.T.; Lamb, A.J. Assessment of the antibacterial activity of galangin against 4-quinolone resistant strains of Staphylococcus aureus. Phytomedicine, 2006, 13(3), 187-191.
[http://dx.doi.org/10.1016/j.phymed.2004.07.003] [PMID: 16428027]
[17]
Shu, Y.S.; Tao, W.; Miao, Q.B.; Lu, S.C.; Zhu, Y.B. Galangin dampens mice lipopolysaccharide-induced acute lung injury. Inflammation, 2014, 37(5), 1661-1668.
[http://dx.doi.org/10.1007/s10753-014-9894-1] [PMID: 24743919]
[18]
Zha, W.J.; Qian, Y.; Shen, Y.; Du, Q.; Chen, F.F.; Wu, Z.Z.; Li, X.; Huang, M. Galangin abrogates ovalbumin-induced airway inflammation via negative regulation of NF- κ. B. Evid. Based Complement. Alternat. Med., 2013, 2013, 1-14.
[http://dx.doi.org/10.1155/2013/767689] [PMID: 23762160]
[19]
Huh, J.E.; Jung, I.T.; Choi, J.; Baek, Y.H.; Lee, J.D.; Park, D.S.; Choi, D.Y. The natural flavonoid galangin inhibits osteoclastic bone destruction and osteoclastogenesis by suppressing NF-κB in collagen-induced arthritis and bone marrow-derived macrophages. Eur. J. Pharmacol., 2013, 698(1-3), 57-66.
[http://dx.doi.org/10.1016/j.ejphar.2012.08.013] [PMID: 22985747]
[20]
Yang, Z.; Li, X.; Han, W.; Lu, X.; Jin, S.; Yang, W.; Li, J.; He, W.; Qian, Y. Galangin suppresses human osteosarcoma cells: An exploration of its underlying mechanism. Oncol. Rep., 2017, 37(1), 435-441.
[http://dx.doi.org/10.3892/or.2016.5224] [PMID: 27840963]
[21]
Zhang, H.T.; Luo, H.; Wu, J.; Lan, L.B.; Fan, D.H.; Zhu, K.D.; Chen, X.Y.; Wen, M.; Liu, H.M. Galangin induces apoptosis of hepatocellular carcinoma cells via the mitochondrial pathway. World J. Gastroenterol., 2010, 16(27), 3377-3384.
[http://dx.doi.org/10.3748/wjg.v16.i27.3377] [PMID: 20632439]
[22]
Liu, D.; You, P.; Luo, Y.; Yang, M.; Liu, Y. Galangin induces apoptosis in mcf-7 human breast cancer cells through mitochondrial pathway and phosphatidylinositol 3-kinase/akt inhibition. Pharmacology, 2018, 102(1-2), 58-66.
[http://dx.doi.org/10.1159/000489564] [PMID: 29879712]
[23]
Kim, D.A.; Jeon, Y.K.; Nam, M.J. Galangin induces apoptosis in gastric cancer cells via regulation of ubiquitin carboxy-terminal hydrolase isozyme L1 and glutathione S-transferase P. Food Chem. Toxicol., 2012, 50(3-4), 684-688.
[http://dx.doi.org/10.1016/j.fct.2011.11.039] [PMID: 22142694]
[24]
Zhu, Y.; Rao, Q.; Zhang, X.; Zhou, X. Galangin induced antitumor effects in human kidney tumor cells mediated via mitochondrial mediated apoptosis, inhibition of cell migration and invasion and targeting PI3K/AKT/mTOR signalling pathway. J. BUON, 2018, 23(3), 795-799.
[PMID: 30003754]
[25]
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]
[26]
Lu, D.; Yang, T.; Tang, N.; Li, C.; Song, Y.; Wang, L.; Wong, W.Y.; Yin, S.F.; Xing, Y.; Kambe, N.; Qiu, R. A pH-dependent rhodamine fluorophore with antiproliferative activity of bladder cancer in vitro/vivo and apoptosis mechanism. Eur. J. Med. Chem., 2022, 236, 114293.
[http://dx.doi.org/10.1016/j.ejmech.2022.114293] [PMID: 35385804]
[27]
Guan, Y.Q.; Li, Z.; Yang, A.; Huang, Z.; Zheng, Z.; Zhang, L.; Li, L.; Liu, J.M. Cell cycle arrest and apoptosis of OVCAR-3 and MCF-7 cells induced by co-immobilized TNF-α plus IFN-γ on polystyrene and the role of p53 activation. Biomaterials, 2012, 33(26), 6162-6171.
[http://dx.doi.org/10.1016/j.biomaterials.2012.05.037] [PMID: 22682938]
[28]
Kuo, Y.C.; Kuo, P.L.; Hsu, Y.L.; Cho, C.Y.; Lin, C.C. Ellipticine induces apoptosis through p53-dependent pathway in human hepatocellular carcinoma HepG2 cells. Life Sci., 2006, 78(22), 2550-2557.
[http://dx.doi.org/10.1016/j.lfs.2005.10.041] [PMID: 16337242]
[29]
Mali, S.N.; Pandey, A. Balanced QSAR and molecular modeling to identify structural requirements of imidazopyridine analogues as anti-infective agents against trypanosomiases. J. Comput. Biophys. Chem., 2022, 21(1), 83-114.
[http://dx.doi.org/10.1142/S2737416521410015]
[30]
Mali, S.N.; Pandey, A. Molecular modeling studies on 2, 4-disubstituted imidazopyridines as anti-malarials: Atom-based 3D-QSAR, molecular docking, virtual screening, in silico ADMET and theoretical analysis. J. Comput. Biophys. Chem., 2021, 20(3), 267-282.
[http://dx.doi.org/10.1142/S2737416521500125]
[31]
Mali, S.N.; Pandey, A. Synthesis of new hydrazones using a biodegradable catalyst, their biological evaluations and molecular modeling studies (part-II). J. Comput. Biophys. Chem., 2022, 21(7), 857-882.
[http://dx.doi.org/10.1142/S2737416522500387]
[32]
Synthesis, molecular docking, antioxidant, anti-tb, and potent mcf7 anticancerstudies of novel aryl-carbohydrazideanalogues. Curr Comput Aided Drug Des, 2022.
[33]
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]
[34]
Yuan, C.; Wang, M.H.; Wang, F.; Chen, P.Y.; Ke, X.G.; Yu, B.; Yang, Y.F.; You, P.T.; Wu, H.Z. Network pharmacology and molecular docking reveal the mechanism of Scopoletin against non-small cell lung cancer. Life Sci., 2021, 270, 119105.
[http://dx.doi.org/10.1016/j.lfs.2021.119105] [PMID: 33497736]
[35]
He, Y.; Xia, Z.; Yu, D.; Wang, J.; Jin, L.; Huang, D.; Ye, X.; Li, X.; Zhang, B. Hepatoprotective effects and structure-activity relationship of five flavonoids against lipopolysaccharide/d-galactosamine induced acute liver failure in mice. Int. Immunopharmacol., 2019, 68, 171-178.
[http://dx.doi.org/10.1016/j.intimp.2018.12.059] [PMID: 30641432]
[36]
Liang, X.; Wang, P.; Yang, C.; Huang, F.; Wu, H.; Shi, H.; Wu, X. Galangin inhibits gastric cancer growth through enhancing stat3 mediated ros production. Front. Pharmacol., 2021, 12, 646628.
[http://dx.doi.org/10.3389/fphar.2021.646628] [PMID: 33981228]
[37]
Grayson, M. Bladder cancer. Nature, 2017, 551(7679), S33.
[http://dx.doi.org/10.1038/551S33a] [PMID: 29117156]
[38]
Hopkins, A.L. Network pharmacology: The next paradigm in drug discovery. Nat. Chem. Biol., 2008, 4(11), 682-690.
[http://dx.doi.org/10.1038/nchembio.118] [PMID: 18936753]
[39]
Li, P.; Nijhawan, D.; Budihardjo, I.; Srinivasula, S.M.; Ahmad, M.; Alnemri, E.S.; Wang, X. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell, 1997, 91(4), 479-489.
[http://dx.doi.org/10.1016/S0092-8674(00)80434-1] [PMID: 9390557]
[40]
Kroemer, G.; Galluzzi, L.; Brenner, C. Mitochondrial membrane permeabilization in cell death. Physiol. Rev., 2007, 87(1), 99-163.
[http://dx.doi.org/10.1152/physrev.00013.2006] [PMID: 17237344]
[41]
Hernández Borrero, L.J.; El-Deiry, W.S. Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting. Biochim. Biophys. Acta Rev. Cancer, 2021, 1876(1), 188556.
[http://dx.doi.org/10.1016/j.bbcan.2021.188556] [PMID: 33932560]
[42]
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]
[43]
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]
[44]
Yang, Y.; Yu, Y.; Wang, J.; Li, Y.; Li, Y.; Wei, J.; Zheng, T.; Jin, M.; Sun, Z. Silica nanoparticles induced intrinsic apoptosis in neuroblastoma SH-SY5Y cells via CytC/Apaf-1 pathway. Environ. Toxicol. Pharmacol., 2017, 52, 161-169.
[http://dx.doi.org/10.1016/j.etap.2017.01.010] [PMID: 28426994]

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