Generic placeholder image

Recent Patents on Anti-Cancer Drug Discovery

Author(s): Chao-yuan Huang, Yi-min Cheng, Wei Li, Yuan-cheng Huang, Hu Luo, Chong Zhong* and Feng-bin Liu*

DOI: 10.2174/1574892817666220511162046

DownloadDownload PDF Flyer Cite As
Examining the Mechanisms of Huachansu Injection on Liver Cancer through Integrated Bioinformatics Analysis

Page: [408 - 425] Pages: 18

  • * (Excluding Mailing and Handling)

Abstract

Objective: The objective of this study is to explore the potential anti-liver cancer mechanism of Huachansu injection through integrated bioinformatics analysis.

Methods: Active ingredients of Huachansu injection (extraction of toad skin) were obtained, and their potential drug targets were predicted via SwissTargetPrediction database. Liver cancer disease targets were identified from the GEO (Gene Expression Omnibus) dataset and four public databases. Then Protein-Protein Interaction (PPI) network of toad skin was constructed. GO (Gene Ontology) enrichment analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis were performed subsequently. Finally, molecular docking was performed using Auto Dock Vina.

Results: In the search for therapeutic targets, twenty active components of toad skin were screened for further study, five hundred and sixty-eight targets of components were identified. In the search for disease targets, three thousand two hundred and twenty-seven genes were identified after removal of duplicated genes, one hundred and fifty-nine genes were up-regulated in liver cancer samples while two hundred and seventy-eight were down-regulated in liver cancer patients. After predicting the therapeutic targets of the components, the results were cross-checked with the disease targets, thirteen up-regulated targets and ten down-regulated targets were obtained. Finally, in the results of molecular docking, seven targets (CDK1, AKR1B1, MMP12, AURKB, CHEK1, AURKA, TTK) were potential up-regulated targets, three targets (SHBG, SRD5A2, NR1I2) were potential down-regulated targets, all of which have the best binding energy and molecular interactions.

Conclusion: CDK1, AKR1B1, MMP12, AURKB, CHEK1, AURKA, and TTK could be potential upregulated target proteins of Huachansu injection for treating liver cancer. The mechanism of Huachansu injection in the treatment of liver cancer through these up-regulated targets is related to cell cycle, cellular senescence, viral carcinogenesis, p53 signaling pathway. SHBG, SRD5A2, and NR1I2 could be potential down-regulated target proteins of Huachansu injection in treating liver cancer.

Keywords: Huachansu injection, hepatocellular carcinoma, effector mechanism network pharmacology, weighted gene co-expression network analysis, molecular docking.

[1]
Sia D, Villanueva A, Friedman SL, Llovet JM. Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology 2017; 152(4): 745-61.
[http://dx.doi.org/10.1053/j.gastro.2016.11.048] [PMID: 28043904]
[2]
Nagtegaal ID, Odze RD, Klimstra D. et al. The 2019 WHO classification of tumours of the digestive system. Histopathology 2020; 76(2): 182-8.
[http://dx.doi.org/10.1111/his.13975] [PMID: 31433515]
[3]
Sung H, Ferlay J, Siegel RL. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71(3): 209-49.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[4]
Losic B, Craig AJ, Villacorta-Martin C. et al. Intratumoral heterogeneity and clonal evolution in liver cancer. Nat Commun 2020; 11(1): 291.
[http://dx.doi.org/10.1038/s41467-019-14050-z] [PMID: 31941899]
[5]
Qi F, Zhao L, Zhou A. et al. The advantages of using traditional Chinese medicine as an adjunctive therapy in the whole course of cancer treatment instead of only terminal stage of cancer. Biosci Trends 2015; 9(1): 16-34.
[http://dx.doi.org/10.5582/bst.2015.01019] [PMID: 25787906]
[6]
Wu J, Zhang D, Ni M. et al. Effectiveness of Huachansu injection combined with chemotherapy for treatment of gastric cancer in China: A systematic review and Meta-analysis. J Tradit Chin Med 2020; 40(5): 749-57.
[PMID: 33000575]
[7]
Rodríguez C, Rollins-Smith L, Ibáñez R, Durant-Archibold AA, Gutiérrez M. Toxins and pharmacologically active compounds from species of the family Bufonidae (Amphibia, Anura). J Ethnopharmacol 2017; 198: 235-54.
[http://dx.doi.org/10.1016/j.jep.2016.12.021] [PMID: 28034659]
[8]
Hopkins AL. Network pharmacology: The next paradigm in drug discovery. Nat Chem Biol 2008; 4(11): 682-90.
[http://dx.doi.org/10.1038/nchembio.118] [PMID: 18936753]
[9]
Langfelder P, Horvath S. WGCNA: An R package for weighted correlation network analysis. BMC Bioinformatics 2008; 9: 559.
[http://dx.doi.org/10.1186/1471-2105-9-559] [PMID: 19114008]
[10]
Ferreira LG, Dos Santos RN, Oliva G, Andricopulo AD. Molecular docking and structure-based drug design strategies. Molecules 2015; 20(7): 13384-421.
[http://dx.doi.org/10.3390/molecules200713384] [PMID: 26205061]
[11]
Hamosh A, Amberger JS, Bocchini C, Scott AF, Rasmussen SA. Online Mendelian Inheritance in Man (OMIM®): Victor McKusick’s magnum opus. Am J Med Genet A 2021; 185(11): 3259-65.
[http://dx.doi.org/10.1002/ajmg.a.62407] [PMID: 34169650]
[12]
Amberger JS, Bocchini CA, Schiettecatte F, Scott AF, Hamosh A. OMIM.org: Online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders. Nucleic Acids Res 2015; 43(Database issue): D789-98.
[http://dx.doi.org/10.1093/nar/gku1205] [PMID: 25428349]
[13]
Piñero J, Bravo À, Queralt-Rosinach N. et al. DisGeNET: A comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Res 2017; 45(D1): D833-9.
[http://dx.doi.org/10.1093/nar/gkw943] [PMID: 27924018]
[14]
Wishart DS, Feunang YD, Guo AC. et al. DrugBank 5.0: A major update to the DrugBank database for 2018. Nucleic Acids Res 2018; 46(D1): D1074-82.
[http://dx.doi.org/10.1093/nar/gkx1037] [PMID: 29126136]
[15]
Safran M, Dalah I, Alexander J. et al. GeneCards Version 3: The human gene integrator. Database (Oxford) 2010; 2010, baq020.
[http://dx.doi.org/10.1093/database/baq020] [PMID: 20689021]
[16]
Meng Q, Yau LF, Lu JG. et al. Chemical profiling and cytotoxicity assay of bufadienolides in toad venom and toad skin. J Ethnopharmacol 2016; 187: 74-82.
[http://dx.doi.org/10.1016/j.jep.2016.03.062] [PMID: 27063985]
[17]
Ren W, Han L, Luo M. et al. Multi-component identification and target cell-based screening of potential bioactive compounds in toad venom by UPLC coupled with high-resolution LTQ-Orbitrap MS and high-sensitivity Qtrap MS. Anal Bioanal Chem 2018; 410(18): 4419-35.
[http://dx.doi.org/10.1007/s00216-018-1097-4] [PMID: 29704033]
[18]
Yang LH, Zhang HZ, Zhang B. et al. Studies on the chemical constituents from the skin of Bufo bufo gargarizans Cantor. Yao Xue Xue Bao 1992; 27(9): 679-83.
[PMID: 1293940]
[19]
Zhou J, Gong Y, Ma H. et al. Effect of drying methods on the free and conjugated bufadienolide content in toad venom determined by ultra-performance liquid chromatography-triple quadrupole mass spectrometry coupled with a pattern recognition approach. J Pharm Biomed Anal 2015; 114: 482-7.
[http://dx.doi.org/10.1016/j.jpba.2015.05.032] [PMID: 26186722]
[20]
Qi F, Li A, Inagaki Y. et al. Antitumor activity of extracts and compounds from the skin of the toad Bufo bufo gargarizans Cantor. Int Immunopharmacol 2011; 11(3): 342-9.
[http://dx.doi.org/10.1016/j.intimp.2010.12.007] [PMID: 21185919]
[21]
Zhao HY, Wu FK, Qiu YK, Wu Z, Jiang YT, Chen JY. Studies on cytotoxic constituents from the skin of the toad Bufo bufo gargarizans. J Asian Nat Prod Res 2010; 12(9): 793-800.
[http://dx.doi.org/10.1080/10286020.2010.505187] [PMID: 20839128]
[22]
Wu FK, Qiu YK, Zhao HY. et al. Cytotoxic constituents from the skin of the toad Bufo bufo gargarizans. J Asian Nat Prod Res 2011; 13(2): 111-6.
[http://dx.doi.org/10.1080/10286020.2010.545350] [PMID: 21279874]
[23]
Wang YM, Li ZY, Wang JJ, Wu XY, Gao HM, Wang ZM. Bufadienolides and polyhydroxycholestane derivatives from Bufo bufo gargarizans. J Asian Nat Prod Res 2015; 17(4): 364-76.
[http://dx.doi.org/10.1080/10286020.2014.995174] [PMID: 25819343]
[24]
Cheng CS, Wang J, Chen J. et al. New therapeutic aspects of steroidal cardiac glycosides: The anticancer properties of Huachansu and its main active constituent Bufalin. Cancer Cell Int 2019; 19: 92.
[http://dx.doi.org/10.1186/s12935-019-0806-1] [PMID: 31011289]
[25]
Zhou B, Wu F, Yuan L, Miao Z, Zhu S. Is Huachansu beneficial in treating advanced non-small-cell lung cancer? Evidence from a meta-analysis of its efficacy combined with chemotherapy. Evid Based Complement Alternat Med 2015; 2015, 408145.
[http://dx.doi.org/10.1155/2015/408145] [PMID: 26347788]
[26]
Qi F, Li A, Inagaki Y. et al. Induction of apoptosis by cinobufacini preparation through mitochondria- and Fas-mediated caspase-dependent pathways in human hepatocellular carcinoma cells. Food Chem Toxicol 2012; 50(2): 295-302.
[http://dx.doi.org/10.1016/j.fct.2011.10.040] [PMID: 22019693]
[27]
Qi F, Inagaki Y, Gao B. et al. Bufalin and cinobufagin induce apoptosis of human hepatocellular carcinoma cells via Fas- and mitochon-dria-mediated pathways. Cancer Sci 2011; 102(5): 951-8.
[http://dx.doi.org/10.1111/j.1349-7006.2011.01900.x] [PMID: 21288283]
[28]
Li Q, Liang RL, Yu QR. et al. Efficacy and safety of cinobufacini injection combined with vinorelbine and cisplatin regimen chemotherapy for stage III/IV non-small cell lung cancer: A protocol for systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore) 2020; 99(31), e21539.
[http://dx.doi.org/10.1097/MD.0000000000021539] [PMID: 32756206]
[29]
Enserink JM, Kolodner RD. An overview of Cdk1-controlled targets and processes. Cell Div 2010; 5: 11.
[http://dx.doi.org/10.1186/1747-1028-5-11] [PMID: 20465793]
[30]
Odle RI, Florey O, Ktistakis NT, Cook SJ. CDK1, the other ‘master regulator’ of autophagy. Trends Cell Biol 2021; 31(2): 95-107.
[http://dx.doi.org/10.1016/j.tcb.2020.11.001] [PMID: 33272830]
[31]
Wu CX, Wang XQ, Chok SH. et al. Blocking CDK1/PDK1/β-Catenin signaling by CDK1 inhibitor RO3306 increased the efficacy of sorafenib treatment by targeting cancer stem cells in a preclinical model of hepatocellular carcinoma. Theranostics 2018; 8(14): 3737-50.
[http://dx.doi.org/10.7150/thno.25487] [PMID: 30083256]
[32]
Zou Y, Ruan S, Jin L. et al. CDK1, CCNB1, and CCNB2 are prognostic biomarkers and correlated with immune infiltration in hepatocellu-lar carcinoma. Med Sci Monit 2020; 26, e925289.
[http://dx.doi.org/10.12659/MSM.925289] [PMID: 32863381]
[33]
Vassilev LT, Tovar C, Chen S. et al. Selective small-molecule inhibitor reveals critical mitotic functions of human CDK1. Proc Natl Acad Sci USA 2006; 103(28): 10660-5.
[http://dx.doi.org/10.1073/pnas.0600447103] [PMID: 16818887]
[34]
Prevo R, Pirovano G, Puliyadi R. et al. CDK1 inhibition sensitizes normal cells to DNA damage in a cell cycle dependent manner. Cell Cycle 2018; 17(12): 1513-23.
[http://dx.doi.org/10.1080/15384101.2018.1491236] [PMID: 30045664]
[35]
Jez JM, Flynn TG, Penning TM. A new nomenclature for the aldo-keto reductase superfamily. Biochem Pharmacol 1997; 54(6): 639-47.
[http://dx.doi.org/10.1016/S0006-2952(97)84253-0] [PMID: 9310340]
[36]
Weber S, Salabei JK, Möller G. et al. Aldo-keto Reductase 1B15 (AKR1B15): A mitochondrial human aldo-keto reductase with activity toward steroids and 3-keto-acyl-CoA conjugates. J Biol Chem 2015; 290(10): 6531-45.
[http://dx.doi.org/10.1074/jbc.M114.610121] [PMID: 25577493]
[37]
Khayami R, Hashemi SR, Kerachian MA. Role of aldo-keto reductase family 1 member B1 (AKR1B1) in the cancer process and its thera-peutic potential. J Cell Mol Med 2020; 24(16): 8890-902.
[http://dx.doi.org/10.1111/jcmm.15581] [PMID: 32633024]
[38]
Ji J, Xu MX, Qian TY. et al. The AKR1B1 inhibitor epalrestat suppresses the progression of cervical cancer. Mol Biol Rep 2020; 47(8): 6091-103.
[http://dx.doi.org/10.1007/s11033-020-05685-z] [PMID: 32761301]
[39]
Lefrançois-Martinez AM, Bertherat J, Val P. et al. Decreased expression of cyclic adenosine monophosphate-regulated aldose reductase (AKR1B1) is associated with malignancy in human sporadic adrenocortical tumors. J Clin Endocrinol Metab 2004; 89(6): 3010-9.
[http://dx.doi.org/10.1210/jc.2003-031830] [PMID: 15181092]
[40]
Pal PB, Sonowal H, Shukla K, Srivastava SK, Ramana KV. Aldose reductase regulates hyperglycemia-induced HUVEC death via SIRT1/AMPK-α1/mTOR pathway. J Mol Endocrinol 2019; 63(1): 11-25.
[http://dx.doi.org/10.1530/JME-19-0080] [PMID: 30986766]
[41]
Lv FZ, Wang JL, Wu Y, Chen HF, Shen XY. Knockdown of MMP12 inhibits the growth and invasion of lung adenocarcinoma cells. Int J Immunopathol Pharmacol 2015; 28(1): 77-84.
[http://dx.doi.org/10.1177/0394632015572557] [PMID: 25816409]
[42]
Chelluboina B, Nalamolu KR, Klopfenstein JD. et al. MMP-12, a promising therapeutic target for neurological diseases. Mol Neurobiol 2018; 55(2): 1405-9.
[http://dx.doi.org/10.1007/s12035-017-0418-5] [PMID: 28155200]
[43]
Shin A, Cai Q, Shu XO, Gao YT. Zhen g W. Genetic polymorphisms in the Matrix Metalloproteinase 12 gene (MMP12) and breast cancer risk and survival: The Shanghai Breast Cancer Study. Breast Cancer Res 2005; 7(4): R506-12.
[http://dx.doi.org/10.1186/bcr1033] [PMID: 15987457]
[44]
He MK, Le Y, Zhang YF. et al. Matrix metalloproteinase 12 expression is associated with tumor FOXP3+ regulatory T cell infiltration and poor prognosis in hepatocellular carcinoma. Oncol Lett 2018; 16(1): 475-82.
[http://dx.doi.org/10.3892/ol.2018.8642] [PMID: 29928435]
[45]
Lin ZZ, Jeng YM, Hu FC. et al. Significance of Aurora B overexpression in hepatocellular carcinoma. Aurora B Overexpression in HCC. BMC Cancer 2010; 10: 461.
[http://dx.doi.org/10.1186/1471-2407-10-461] [PMID: 20799978]
[46]
Wan B, Huang Y, Liu B, Lu L, Lv C. AURKB: A promising biomarker in clear cell renal cell carcinoma. PeerJ 2019; 7, e7718.
[http://dx.doi.org/10.7717/peerj.7718] [PMID: 31576249]
[47]
Nie M, Wang Y, Yu Z. et al. AURKB promotes gastric cancer progression via activation of CCND1 expression. Aging (Albany NY) 2020; 12(2): 1304-21.
[http://dx.doi.org/10.18632/aging.102684] [PMID: 31982864]
[48]
Wang-Bishop L, Chen Z, Gomaa A. et al. Inhibition of AURKA reduces proliferation and survival of gastrointestinal cancer cells with activated KRAS by preventing activation of RPS6KB1. Gastroenterology 2019; 156(3): 662-675.e7.
[http://dx.doi.org/10.1053/j.gastro.2018.10.030] [PMID: 30342037]
[49]
McNeely S, Beckmann R, Bence Lin AK. CHEK again: Revisiting the development of CHK1 inhibitors for cancer therapy. Pharmacol Ther 2014; 142(1): 1-10.
[http://dx.doi.org/10.1016/j.pharmthera.2013.10.005] [PMID: 24140082]
[50]
Gong D, Feng PC, Ke XF. et al. Silencing long non-coding RNA LINC01224 inhibits hepatocellular carcinoma progression via MicroRNA-330-5p-induced inhibition of CHEK1. Mol Ther Nucleic Acids 2020; 19: 482-97.
[http://dx.doi.org/10.1016/j.omtn.2019.10.007] [PMID: 31902747]
[51]
Simó R, Sáez-López C, Barbosa-Desongles A, Hernández C, Selva DM. Novel insights in SHBG regulation and clinical implications. Trends Endocrinol Metab 2015; 26(7): 376-83.
[http://dx.doi.org/10.1016/j.tem.2015.05.001] [PMID: 26044465]
[52]
Thaler MA, Seifert-Klauss V, Luppa PB. The biomarker sex hormone-binding globulin - from established applications to emerging trends in clinical medicine. Best Pract Res Clin Endocrinol Metab 2015; 29(5): 749-60.
[http://dx.doi.org/10.1016/j.beem.2015.06.005] [PMID: 26522459]
[53]
Deswal R, Yadav A, Dang AS. Sex hormone binding globulin - an important biomarker for predicting PCOS risk: A systematic review and meta-analysis. Syst Biol Reprod Med 2018; 64(1): 12-24.
[http://dx.doi.org/10.1080/19396368.2017.1410591] [PMID: 29227165]
[54]
Ramos L, Vilchis F, Chávez B, Mares L. Mutational analysis of SRD5A2: From gene to functional kinetics in individuals with steroid 5α-reductase 2 deficiency. J Steroid Biochem Mol Biol 2020; 200, 105691.
[http://dx.doi.org/10.1016/j.jsbmb.2020.105691] [PMID: 32380235]
[55]
Okeigwe I, Kuohung W. 5-Alpha reductase deficiency: A 40-year retrospective review. Curr Opin Endocrinol Diabetes Obes 2014; 21(6): 483-7.
[http://dx.doi.org/10.1097/MED.0000000000000116] [PMID: 25321150]
[56]
Li J, Coates RJ, Gwinn M, Khoury MJ. Steroid 5-alpha-reductase Type 2 (SRD5a2) gene polymorphisms and risk of prostate cancer: A HuGE review. Am J Epidemiol 2010; 171(1): 1-13.
[http://dx.doi.org/10.1093/aje/kwp318] [PMID: 19914946]
[57]
Fang C, Guo ZQ, Chen XY, Liu TZ, Zeng XT, Wang XH. Relationship between SRD5A2 rs9282858 polymorphism and the susceptibility of prostate cancer: A meta-analysis based on 20 publications. Medicine (Baltimore) 2017; 96(19), e6791.
[http://dx.doi.org/10.1097/MD.0000000000006791] [PMID: 28489754]
[58]
Moribe T, Iizuka N, Miura T. et al. Identification of novel aberrant methylation of BASP1 and SRD5A2 for early diagnosis of hepatocellular carcinoma by genome-wide search. Int J Oncol 2008; 33(5): 949-58.
[PMID: 18949357]
[59]
Tsunedomi R, Ogawa Y, Iizuka N. et al. The assessment of methylated BASP1 and SRD5A2 levels in the detection of early hepatocellular carcinoma. Int J Oncol 2010; 36(1): 205-12.
[PMID: 19956849]
[60]
Wang XD, Li JL, Su QB. et al. A pharmacogenetic study of pregnane X receptor (NR1I2) in Han Chinese. Curr Drug Metab 2007; 8(8): 778-86.
[http://dx.doi.org/10.2174/138920007782798199] [PMID: 18220558]
[61]
Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol 2018; 28(6): 436-53.
[http://dx.doi.org/10.1016/j.tcb.2018.02.001] [PMID: 29477613]
[62]
Chen Y, Williams V, Filippova M, Filippov V, Duerksen-Hughes P. Viral carcinogenesis: Factors inducing DNA damage and virus integration. Cancers (Basel) 2014; 6(4): 2155-86.
[http://dx.doi.org/10.3390/cancers6042155] [PMID: 25340830]
[63]
Rahman N, Khan H, Zia A. et al. Bcl-2 Modulation in p53 signaling pathway by flavonoids: A potential strategy towards the treatment of cancer. Int J Mol Sci 2021; 22(21): 11315.
[http://dx.doi.org/10.3390/ijms222111315] [PMID: 34768743]
[64]
Shen E, Zhang J, Lu Y. DEP Domain Containing 1B (DEPDC1B) exerts the tumor promoter in hepatocellular carcinoma through activating p53 signaling pathway via kinesin family member 23 (KIF23). Bioengineered 2022; 13(1): 1103-14.
[http://dx.doi.org/10.1080/21655979.2021.2017629] [PMID: 34983303]