<?xml version="1.0" encoding="UTF-8"?>
<!DOCTYPE root>
<article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:ali="http://www.niso.org/schemas/ali/1.0/" article-type="research-article" dtd-version="1.2" xml:lang="en"><front><journal-meta><journal-id journal-id-type="publisher-id">Combinatorial Chemistry &amp; High Throughput Screening</journal-id><journal-title-group><journal-title xml:lang="en">Combinatorial Chemistry &amp; High Throughput Screening</journal-title><trans-title-group xml:lang="ru"><trans-title>Combinatorial Chemistry &amp; High Throughput Screening</trans-title></trans-title-group></journal-title-group><issn publication-format="print">1386-2073</issn><issn publication-format="electronic">1875-5402</issn><publisher><publisher-name xml:lang="en">Bentham Science</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="publisher-id">643920</article-id><article-id pub-id-type="doi">10.2174/0113862073294990240122140121</article-id><article-categories><subj-group subj-group-type="toc-heading"><subject>Chemistry</subject></subj-group><subj-group subj-group-type="article-type"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title xml:lang="en">The Role of Emodin in the Treatment of Bladder Cancer Based on Network Pharmacology and Experimental Verification</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Fule</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff1"/></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Jianghao</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff1"/></contrib><contrib contrib-type="author"><name><surname>Zhou</surname><given-names>Boruo</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff1"/></contrib><contrib contrib-type="author"><name><surname>Shen</surname><given-names>Yang</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff2"/></contrib><contrib contrib-type="author"><name><surname>Tang</surname><given-names>Jingyuan</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff3"/></contrib><contrib contrib-type="author"><name><surname>Han</surname><given-names>Jie</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff3"/></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Changpeng</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff3"/></contrib><contrib contrib-type="author"><name><surname>Shao</surname><given-names>Kang</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff1"/></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Haojie</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff4"/></contrib><contrib contrib-type="author"><name><surname>Yuan</surname><given-names>Lin</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff3"/></contrib></contrib-group><aff id="aff1"><institution>The First Clinical Medical College, Nanjing University of Chinese Medicine</institution></aff><aff id="aff2"><institution>Department of Urology,, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Second Chinese Medicine Hospital</institution></aff><aff id="aff3"><institution>Department of Urology, The Affiliated Hospital of Nanjing University of Chinese Medicine</institution></aff><aff id="aff4"><institution>The First Clinical Medical College,, Nanjing University of Chinese Medicine</institution></aff><pub-date date-type="pub" iso-8601-date="2024-06-01" publication-format="electronic"><day>01</day><month>06</month><year>2024</year></pub-date><volume>27</volume><issue>11</issue><issue-title xml:lang="ru"/><fpage>1661</fpage><lpage>1675</lpage><history><date date-type="received" iso-8601-date="2025-01-07"><day>07</day><month>01</month><year>2025</year></date></history><permissions><copyright-statement xml:lang="en">Copyright ©; 2024, Bentham Science Publishers</copyright-statement><copyright-year>2024</copyright-year><copyright-holder xml:lang="en">Bentham Science Publishers</copyright-holder><ali:free_to_read xmlns:ali="http://www.niso.org/schemas/ali/1.0/"/></permissions><self-uri xlink:href="https://rjpbr.com/1386-2073/article/view/643920">https://rjpbr.com/1386-2073/article/view/643920</self-uri><abstract xml:lang="en"><p id="idm46041443736048">Background and Purpose:Emodin, a compound derived from rhubarb and various traditional Chinese medicines, exhibits a range of pharmacological actions, including antiinflammatory, antiviral, and anticancer properties. Nevertheless, its pharmacological impact on bladder cancer (BLCA) and the underlying mechanism are still unclear. This research aimed to analyze the pharmacological mechanisms of Emodin against BLCA using network pharmacology analysis and experimental verification.</p><p id="idm46041443740048">Methods::Initially, network pharmacology was employed to identify core targets and associated pathways affected by Emodin in bladder cancer. Subsequently, the expression of key targets in normal bladder tissues and BLCA tissues was assessed by searching the GEPIA and HPA databases. The binding energy between Emodin and key targets was predicted using molecular docking. Furthermore, in vitro experiments were carried out to confirm the predictions made with network pharmacology.</p><p id="idm46041443744016">Results::Our analysis identified 148 common genes targeted by Emodin and BLCA, with the top ten target genes including TP53, HSP90AA1, EGFR, MYC, CASP3, CDK1, PTPN11, EGF, ESR1, and TNF. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated a significant correlation between Emodin and the PI3KAKT pathway in the context of BLCA. Molecular docking investigations revealed a strong affinity between Emodin and critical target proteins. In vitro experiments demonstrated that Emodin inhibits T24 proliferation, migration, and invasion while inducing cell apoptosis. The findings also indicated that Emodin reduces both PI3K and AKT protein and mRNA expression, suggesting that Emodin may mitigate BLCA by modulating the PI3K-AKT signaling pathway.</p><p id="idm46041443749072">Conclusion::This study integrates network pharmacology with in vitro experimentation to elucidate the potential mechanisms underlying the action of Emodin against BLCA. The results of this research enhance our understanding of the pharmacological mechanisms by which Emodin may be employed in treating BLCA.</p></abstract><kwd-group xml:lang="en"><kwd>Bladder cancer</kwd><kwd>emodin</kwd><kwd>network pharmacology</kwd><kwd>molecular docking</kwd><kwd>molecular mechanism</kwd><kwd>experimental verification.</kwd></kwd-group></article-meta></front><body></body><back><ref-list><ref id="B1"><label>1.</label><mixed-citation>Frick, C.; Rumgay, H.; Vignat, J.; Ginsburg, O.; Nolte, E.; Bray, F.; Soerjomataram, I. Quantitative estimates of preventable and treatable deaths from 36 cancers worldwide: A population-based study. Lancet Glob. Health, 2023, 11(11), e1700-e1712. doi: 10.1016/S2214-109X(23)00406-0 PMID: 37774721</mixed-citation></ref><ref id="B2"><label>2.</label><mixed-citation>Zhang, H.; Zhou, C.; Zhang, Z.; Yao, S.; Bian, Y.; Fu, F.; Luo, H.; Li, Y.; Yan, S.; Ge, Y.; Chen, Y.; Zhan, K.; Yue, M.; Du, W.; Tian, K.; Jin, H.; Li, X.; Tong, P.; Ruan, H.; Wu, C. Integration of network pharmacology and experimental validation to explore the pharmacological mechanisms of zhuanggu busui formula against osteoporosis. Front. Endocrinol., 2022, 12, 841668. doi: 10.3389/fendo.2021.841668 PMID: 35154014</mixed-citation></ref><ref id="B3"><label>3.</label><mixed-citation>Dong, X.; Zeng, Y.; Liu, Y.; You, L.; Yin, X.; Fu, J.; Ni, J. Aloe-emodin: A review of its pharmacology, toxicity, and pharmacokinetics. Phytother. Res., 2020, 34(2), 270-281. doi: 10.1002/ptr.6532 PMID: 31680350</mixed-citation></ref><ref id="B4"><label>4.</label><mixed-citation>Chen, S.; Zhang, Z.; Zhang, J. Emodin enhances antitumor effect of paclitaxel on human non-small-cell lung cancer cells in vitro and in vivo. Drug Des. Devel. Ther., 2019, 13, 1145-1153. doi: 10.2147/DDDT.S196319 PMID: 31114158</mixed-citation></ref><ref id="B5"><label>5.</label><mixed-citation>Dai, G.; Ding, K.; Cao, Q.; Xu, T.; He, F.; Liu, S.; Ju, W. Emodin suppresses growth and invasion of colorectal cancer cells by inhibiting VEGFR2. Eur. J. Pharmacol., 2019, 859, 172525. doi: 10.1016/j.ejphar.2019.172525 PMID: 31288005</mixed-citation></ref><ref id="B6"><label>6.</label><mixed-citation>Shi, G.H.; Zhou, L. Emodin suppresses angiogenesis and metastasis in anaplastic thyroid cancer by affecting TRAF6 mediated pathways in-vivo and in-vitro. Mol. Med. Rep., 2018, 18(6), 5191-5197. doi: 10.3892/mmr.2018.9510 PMID: 30272291</mixed-citation></ref><ref id="B7"><label>7.</label><mixed-citation>Hao, D.C.; Xiao, P.G. Network pharmacology: A Rosetta Stone for traditional Chinese medicine. Drug Dev. Res., 2014, 75(5), 299-312. doi: 10.1002/ddr.21214 PMID: 25160070</mixed-citation></ref><ref id="B8"><label>8.</label><mixed-citation>Zheng, J.; Wu, M.; Wang, H.; Li, S.; Wang, X.; Li, Y.; Wang, D.; Li, S. Network pharmacology to unveil the biological basis of health-strengthening herbal medicine in cancer treatment. Cancers, 2018, 10(11), 461. doi: 10.3390/cancers10110461 PMID: 30469422</mixed-citation></ref><ref id="B9"><label>9.</label><mixed-citation>Kim, S.; Chen, J.; Cheng, T.; Gindulyte, A.; He, J.; He, S.; Li, Q.; Shoemaker, B.A.; Thiessen, P.A.; Yu, B.; Zaslavsky, L.; Zhang, J.; Bolton, E.E. PubChem 2023 update. Nucleic Acids Res., 2023, 51(D1), D1373-D1380. doi: 10.1093/nar/gkac956 PMID: 36305812</mixed-citation></ref><ref id="B10"><label>10.</label><mixed-citation>Gallo, K.; Goede, A.; Preissner, R.; Gohlke, B.O. SuperPred 3.0: Drug classification and target predictiona machine learning approach. Nucleic Acids Res., 2022, 50(W1), W726-W731. doi: 10.1093/nar/gkac297 PMID: 35524552</mixed-citation></ref><ref id="B11"><label>11.</label><mixed-citation>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. doi: 10.1093/nar/gkz382 PMID: 31106366</mixed-citation></ref><ref id="B12"><label>12.</label><mixed-citation>Ru, J.; Li, P.; Wang, J.; Zhou, W.; Li, B.; Huang, C.; Li, P.; Guo, Z.; Tao, W.; Yang, Y.; Xu, X.; Li, Y.; Wang, Y.; Yang, L. TCMSP: A database of systems pharmacology for drug discovery from herbal medicines. J. Cheminform., 2014, 6(1), 13. doi: 10.1186/1758-2946-6-13 PMID: 24735618</mixed-citation></ref><ref id="B13"><label>13.</label><mixed-citation>Bateman, A.; Martin, M-J.; Orchard, S.; Magrane, M.; Agivetova, R.; Ahmad, S.; Alpi, E.; Bowler-Barnett, E.H.; Britto, R.; Bursteinas, B.; Bye-A-Jee, H.; Coetzee, R.; Cukura, A.; Da Silva, A.; Denny, P.; Dogan, T.; Ebenezer, T.G.; Fan, J.; Castro, L.G.; Garmiri, P.; Georghiou, G.; Gonzales, L.; Hatton-Ellis, E.; Hussein, A.; Ignatchenko, A.; Insana, G.; Ishtiaq, R.; Jokinen, P.; Joshi, V.; Jyothi, D.; Lock, A.; Lopez, R.; Luciani, A.; Luo, J.; Lussi, Y.; MacDougall, A.; Madeira, F.; Mahmoudy, M.; Menchi, M.; Mishra, A.; Moulang, K.; Nightingale, A.; Oliveira, C.S.; Pundir, S.; Qi, G.; Raj, S.; Rice, D.; Lopez, M.R.; Saidi, R.; Sampson, J.; Sawford, T.; Speretta, E.; Turner, E.; Tyagi, N.; Vasudev, P.; Volynkin, V.; Warner, K.; Watkins, X.; Zaru, R.; Zellner, H.; Bridge, A.; Poux, S.; Redaschi, N.; Aimo, L.; Argoud-Puy, G.; Auchincloss, A.; Axelsen, K.; Bansal, P.; Baratin, D.; Blatter, M-C.; Bolleman, J.; Boutet, E.; Breuza, L.; Casals-Casas, C.; de Castro, E.; Echioukh, K.C.; Coudert, E.; Cuche, B.; Doche, M.; Dornevil, D.; Estreicher, A.; Famiglietti, M.L.; Feuermann, M.; Gasteiger, E.; Gehant, S.; Gerritsen, V.; Gos, A.; Gruaz-Gumowski, N.; Hinz, U.; Hulo, C.; Hyka-Nouspikel, N.; Jungo, F.; Keller, G.; Kerhornou, A.; Lara, V.; Le Mercier, P.; Lieberherr, D.; Lombardot, T.; Martin, X.; Masson, P.; Morgat, A.; Neto, T.B.; Paesano, S.; Pedruzzi, I.; Pilbout, S.; Pourcel, L.; Pozzato, M.; Pruess, M.; Rivoire, C.; Sigrist, C.; Sonesson, K.; Stutz, A.; Sundaram, S.; Tognolli, M.; Verbregue, L.; Wu, C.H.; Arighi, C.N.; Arminski, L.; Chen, C.; Chen, Y.; Garavelli, J.S.; Huang, H.; Laiho, K.; McGarvey, P.; Natale, D.A.; Ross, K.; Vinayaka, C.R.; Wang, Q.; Wang, Y.; Yeh, L-S.; Zhang, J.; Ruch, P.; Teodoro, D. UniProt: The universal protein knowledgebase in 2021. Nucleic Acids Res., 2021, 49(D1), D480-D489. doi: 10.1093/nar/gkaa1100 PMID: 33237286</mixed-citation></ref><ref id="B14"><label>14.</label><mixed-citation>Amberger, J.S.; Bocchini, C.A.; Scott, A.F.; Hamosh, A. OMIM.org: Leveraging knowledge across phenotypegene relationships. Nucleic Acids Res., 2019, 47(D1), D1038-D1043. doi: 10.1093/nar/gky1151 PMID: 30445645</mixed-citation></ref><ref id="B15"><label>15.</label><mixed-citation>Stelzer, G; Plaschkes, I; Oz-Levi, D; Alkelai, A; Olender, T; Zimmerman, S; Twik, M; Belinky, F; Fishilevich, S; Nudel, R VarElect: The phenotype-based variation prioritizer of the genecards suite. BMC Genomics, 2016, 17(Suppl 2), 444. doi: 10.1186/s12864-016-2722-2</mixed-citation></ref><ref id="B16"><label>16.</label><mixed-citation>Piñero, J.; Ramírez-Anguita, J.M.; Saüch-Pitarch, J.; Ronzano, F.; Centeno, E.; Sanz, F.; Furlong, L.I. The DisGeNET knowledge platform for disease genomics: 2019 update. Nucleic Acids Res., 2020, 48(D1), D845-D855. PMID: 31680165</mixed-citation></ref><ref id="B17"><label>17.</label><mixed-citation>Sherman, B.T.; Hao, M.; Qiu, J.; Jiao, X.; Baseler, M.W.; Lane, H.C.; Imamichi, T.; Chang, W. DAVID: A web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res., 2022, 50(W1), W216-W221. doi: 10.1093/nar/gkac194 PMID: 35325185</mixed-citation></ref><ref id="B18"><label>18.</label><mixed-citation>Meng, X.Y.; Zhang, H.X.; Mezei, M.; Cui, M. Molecular docking: A powerful approach for structure-based drug discovery. Curr. Computeraided Drug Des., 2011, 7(2), 146-157. doi: 10.2174/157340911795677602 PMID: 21534921</mixed-citation></ref><ref id="B19"><label>19.</label><mixed-citation>Notarte, K.I.R.; Quimque, M.T.J.; Macaranas, I.T.; Khan, A.; Pastrana, A.M.; Villaflores, O.B.; Arturo, H.C.P.; Pilapil, D.Y.H., IV; Tan, S.M.M.; Wei, D.Q.; Wenzel-Storjohann, A.; Tasdemir, D.; Yen, C.H.; Ji, S.Y.; Kim, G.Y.; Choi, Y.H.; Macabeo, A.P.G. Attenuation of lipopolysaccharide-induced inflammatory responses through inhibition of the NF-κB pathway and the increased NRF2 level by a flavonol-enriched n -butanol fraction from uvaria alba. ACS Omega, 2023, 8(6), 5377-5392. doi: 10.1021/acsomega.2c06451 PMID: 36816691</mixed-citation></ref><ref id="B20"><label>20.</label><mixed-citation>Quimque, M.T.; Notarte, K.I.; Letada, A.; Fernandez, R.A.; Pilapil, D.Y., IV; Pueblos, K.R.; Agbay, J.C.; Dahse, H.M.; Wenzel-Storjohann, A.; Tasdemir, D.; Khan, A.; Wei, D.Q.; Gose Macabeo, A.P. Potential cancer- and alzheimers disease-targeting phosphodiesterase inhibitors from uvaria alba: Insights from in vitro and consensus virtual screening. ACS Omega, 2021, 6(12), 8403-8417. doi: 10.1021/acsomega.1c00137 PMID: 33817501</mixed-citation></ref><ref id="B21"><label>21.</label><mixed-citation>Carmo Bastos, M.L.; Silva-Silva, J.V.; Neves Cruz, J.; Palheta da Silva, A.R.; Bentaberry-Rosa, A.A.; da Costa Ramos, G.; de Sousa Siqueira, J.E.; Coelho-Ferreira, M.R.; Percário, S.; Santana Barbosa Marinho, P.; Marinho, A.M.R.; de Oliveira Bahia, M.; Dolabela, M.F. Alkaloid from Geissospermum sericeum Benth. &amp; Hook.f. ex Miers (Apocynaceae) Induce apoptosis by caspase pathway in human gastric cancer cells. Pharmaceuticals, 2023, 16(5), 765. doi: 10.3390/ph16050765 PMID: 37242548</mixed-citation></ref><ref id="B22"><label>22.</label><mixed-citation>de Almeida, R.B.M.; Barbosa, D.B.; do Bomfim, M.R.; Amparo, J.A.O.; Andrade, B.S.; Costa, S.L.; Campos, J.M.; Cruz, J.N.; Santos, C.B.R.; Leite, F.H.A.; Botura, M.B. Identification of a novel dual inhibitor of acetylcholinesterase and butyrylcholinesterase: In vitro and in silico studies. Pharmaceuticals, 2023, 16(1), 95. doi: 10.3390/ph16010095 PMID: 36678592</mixed-citation></ref><ref id="B23"><label>23.</label><mixed-citation>Hiebl, V.; Ladurner, A.; Latkolik, S.; Dirsch, V.M. Natural products as modulators of the nuclear receptors and metabolic sensors LXR, FXR and RXR. Biotechnol. Adv., 2018, 36(6), 1657-1698. doi: 10.1016/j.biotechadv.2018.03.003 PMID: 29548878</mixed-citation></ref><ref id="B24"><label>24.</label><mixed-citation>Ramos, INdF.; da Silva, MF.; Lopes, JMS.; Cruz, JN.; Alves, FS.; do Rego, JdAR.; Costa, MLd.; Assumpção, PPd.; Barros Brasil, DdS.; Khayat, AS. Extraction, characterization, and evaluation of the cytotoxic activity of piperine in its isolated form and in combination with chemotherapeutics against gastric cancer. Molecules, 2023, 28(14)</mixed-citation></ref><ref id="B25"><label>25.</label><mixed-citation>Shahane, K.; Kshirsagar, M.; Tambe, S.; Jain, D.; Rout, S.; Ferreira, M.K.M.; Mali, S.; Amin, P.; Srivastav, P.P.; Cruz, J.; Lima, R.R. An updated review on the multifaceted therapeutic potential of calendula officinalis L. Pharmaceuticals, 2023, 16(4), 611. doi: 10.3390/ph16040611 PMID: 37111369</mixed-citation></ref><ref id="B26"><label>26.</label><mixed-citation>Berger, S.I.; Iyengar, R. Network analyses in systems pharmacology. Bioinformatics, 2009, 25(19), 2466-2472. doi: 10.1093/bioinformatics/btp465 PMID: 19648136</mixed-citation></ref><ref id="B27"><label>27.</label><mixed-citation>Macabeo, A.P.; Quimque, M.T.; Notarte, K.I.; Adviento, X.A.; Cabunoc, M.H.; de Leon, V.N.; delos Reyes, F.S.L.; Lugtu, E.J.; Manzano, J.A.; Monton, S.N.; Muñoz, J.E.; Ong, K.D.; Pilapil, D.Y.; Roque, V.; Tan, S.M.; Lim, J.A. Polyphenolic natural products active in silico against SARS-CoV-2 spike receptor binding domains and non-structural proteins - A review. Comb. Chem. High Throughput Screen., 2023, 26(3), 459-488. doi: 10.2174/1386207325666210917113207 PMID: 34533442</mixed-citation></ref><ref id="B28"><label>28.</label><mixed-citation>Cui, W.; Aouidate, A.; Wang, S.; Yu, Q.; Li, Y.; Yuan, S. Discovering anti-cancer drugs via computational methods. Front. Pharmacol., 2020, 11, 733. doi: 10.3389/fphar.2020.00733 PMID: 32508653</mixed-citation></ref><ref id="B29"><label>29.</label><mixed-citation>Huang, Z.; Yao, X.J.; Gu, R.X. Editorial: Computational approaches in drug discovery and precision medicine. Front Chem., 2021, 8, 639449. doi: 10.3389/fchem.2020.639449 PMID: 33659236</mixed-citation></ref><ref id="B30"><label>30.</label><mixed-citation>Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7(1), 42717. doi: 10.1038/srep42717 PMID: 28256516</mixed-citation></ref><ref id="B31"><label>31.</label><mixed-citation>Fernandez, R.A.; Quimque, M.T.; Notarte, K.I.; Manzano, J.A.; Pilapil, D.Y., IV; de Leon, V.N.; San Jose, J.J.; Villalobos, O.; Muralidharan, N.H.; Gromiha, M.M.; Brogi, S.; Macabeo, A.P.G. Myxobacterial depsipeptide chondramides interrupt SARS-CoV-2 entry by targeting its broad, cell tropic spike protein. J. Biomol. Struct. Dyn., 2022, 40(22), 12209-12220. doi: 10.1080/07391102.2021.1969281 PMID: 34463219</mixed-citation></ref><ref id="B32"><label>32.</label><mixed-citation>Brogi, S.; Quimque, M.T.; Notarte, K.I.; Africa, J.G.; Hernandez, J.B.; Tan, S.M.; Calderone, V.; Macabeo, A.P. Virtual combinatorial library screening of quinadoline B derivatives against SARS-CoV-2 RNA-dependent RNA polymerase. Computation, 2022, 10(1), 7. doi: 10.3390/computation10010007</mixed-citation></ref><ref id="B33"><label>33.</label><mixed-citation>Wu, G.; Wang, F.; Li, K.; Li, S.; Zhao, C.; Fan, C.; Wang, J. Significance of TP53 mutation in bladder cancer disease progression and drug selection. PeerJ, 2019, 7, e8261. doi: 10.7717/peerj.8261 PMID: 31871844</mixed-citation></ref><ref id="B34"><label>34.</label><mixed-citation>Li, Q.Q.; Hao, J.J.; Zhang, Z.; Krane, L.S.; Hammerich, K.H.; Sanford, T.; Trepel, J.B.; Neckers, L.; Agarwal, P.K. Proteomic analysis of proteome and histone post-translational modifications in heat shock protein 90 inhibition-mediated bladder cancer therapeutics. Sci. Rep., 2017, 7(1), 201. doi: 10.1038/s41598-017-00143-6 PMID: 28298630</mixed-citation></ref><ref id="B35"><label>35.</label><mixed-citation>Mason, R.A.; Morlock, E.V.; Karagas, M.R.; Kelsey, K.T.; Marsit, C.J.; Schned, A.R.; Andrew, A.S. EGFR pathway polymorphisms and bladder cancer susceptibility and prognosis. Carcinogenesis, 2009, 30(7), 1155-1160. doi: 10.1093/carcin/bgp077 PMID: 19372140</mixed-citation></ref><ref id="B36"><label>36.</label><mixed-citation>Rubio, K.; Romero-Olmedo, A.J.; Sarvari, P.; Swaminathan, G.; Ranvir, V.P.; Rogel-Ayala, D.G.; Cordero, J.; Günther, S.; Mehta, A.; Bassaly, B.; Braubach, P.; Wygrecka, M.; Gattenlöhner, S.; Tresch, A.; Braun, T.; Dobreva, G.; Rivera, M.N.; Singh, I.; Graumann, J.; Barreto, G. Non-canonical integrin signaling activates EGFR and RAS-MAPK-ERK signaling in small cell lung cancer. Theranostics, 2023, 13(8), 2384-2407. doi: 10.7150/thno.79493 PMID: 37215577</mixed-citation></ref><ref id="B37"><label>37.</label><mixed-citation>Hartleben, G.; Müller, C.; Krämer, A.; Schimmel, H.; Zidek, L.M.; Dornblut, C.; Winkler, R.; Eichwald, S.; Kortman, G.; Kosan, C.; Kluiver, J.; Petersen, I.; van den Berg, A.; Wang, Z.Q.; Calkhoven, C.F. Tuberous sclerosis complex is required for tumor maintenance in MYC-driven Burkitts lymphoma. EMBO J., 2018, 37(21), e98589. doi: 10.15252/embj.201798589 PMID: 30237309</mixed-citation></ref><ref id="B38"><label>38.</label><mixed-citation>Jiménez-Vidal, L.; Espitia-Pérez, P.; Torres-Ávila, J.; Ricardo-Caldera, D.; Salcedo-Arteaga, S.; Galeano-Páez, C.; Pastor-Sierra, K.; Espitia-Pérez, L. Nuclear factor erythroid 2  related factor 2 and its relationship with cellular response in nickel exposure: A systems biology analysis. BMC Pharmacol. Toxicol., 2019, 20(S1)(Suppl. 1), 78. doi: 10.1186/s40360-019-0360-4 PMID: 31852525</mixed-citation></ref><ref id="B39"><label>39.</label><mixed-citation>Lin, B.; Zhu, M.; Wang, W.; Li, W.; Dong, X.; Chen, Y.; Lu, Y.; Guo, J.; Li, M. Structural basis for alpha fetoprotein-mediated inhibition of caspase-3 activity in hepatocellular carcinoma cells. Int. J. Cancer, 2017, 141(7), 1413-1421. doi: 10.1002/ijc.30850 PMID: 28653316</mixed-citation></ref><ref id="B40"><label>40.</label><mixed-citation>Lakhani, S.A.; Masud, A.; Kuida, K.; Porter, G.A., Jr; Booth, C.J.; Mehal, W.Z.; Inayat, I.; Flavell, R.A. Caspases 3 and 7: Key mediators of mitochondrial events of apoptosis. Science, 2006, 311(5762), 847-851. doi: 10.1126/science.1115035 PMID: 16469926</mixed-citation></ref><ref id="B41"><label>41.</label><mixed-citation>Yamamura, M.; Sato, Y.; Takahashi, K.; Sasaki, M.; Harada, K. The cyclin-dependent kinase pathway involving CDK1 is a potential therapeutic target for cholangiocarcinoma. Oncol. Rep., 2020, 43(1), 306-317. PMID: 31746435</mixed-citation></ref><ref id="B42"><label>42.</label><mixed-citation>Heo, J.; Lee, J.; Nam, Y.J.; Kim, Y.; Yun, H.; Lee, S.; Ju, H.; Ryu, C.M.; Jeong, S.M.; Lee, J.; Lim, J.; Cho, Y.M.; Jeong, E.M.; Hong, B.; Son, J.; Shin, D.M. The CDK1/TFCP2L1/ID2 cascade offers a novel combination therapy strategy in a preclinical model of bladder cancer. Exp. Mol. Med., 2022, 54(6), 801-811. doi: 10.1038/s12276-022-00786-0 PMID: 35729325</mixed-citation></ref><ref id="B43"><label>43.</label><mixed-citation>Rehman, A.U.; Rahman, M.U.; Khan, M.T.; Saud, S.; Liu, H.; Song, D.; Sultana, P.; Wadood, A.; Chen, H.F. The landscape of protein tyrosine phosphatase (Shp2) and cancer. Curr. Pharm. Des., 2019, 24(32), 3767-3777. doi: 10.2174/1381612824666181106100837 PMID: 30398108</mixed-citation></ref><ref id="B44"><label>44.</label><mixed-citation>Su, W.P.; Tu, I.H.; Hu, S.W.; Yeh, H.H.; Shieh, D.B.; Chen, T.Y.; Su, W.C. HER-2/neu raises SHP-2, stops IFN-γ anti-proliferation in bladder cancer. Biochem. Biophys. Res. Commun., 2007, 356(1), 181-186. doi: 10.1016/j.bbrc.2007.02.099 PMID: 17346677</mixed-citation></ref><ref id="B45"><label>45.</label><mixed-citation>Martin-Way, D.; Puche-Sanz, I.; Cozar, J.M.; Zafra-Gomez, A.; Gomez-Regalado, M.D.C.; Morales-Alvarez, C.M.; Hernandez, A.F.; Martinez-Gonzalez, L.J.; Alvarez-Cubero, M.J. Genetic variants of antioxidant enzymes and environmental exposures as molecular biomarkers associated with the risk and aggressiveness of bladder cancer. Sci. Total Environ., 2022, 843, 156965. doi: 10.1016/j.scitotenv.2022.156965 PMID: 35764155</mixed-citation></ref><ref id="B46"><label>46.</label><mixed-citation>Dash, S.; Sahu, A.K.; Srivastava, A.; Chowdhury, R.; Mukherjee, S. Exploring the extensive crosstalk between the antagonistic cytokines- TGF-β and TNF-α in regulating cancer pathogenesis. Cytokine, 2021, 138, 155348. doi: 10.1016/j.cyto.2020.155348 PMID: 33153895</mixed-citation></ref><ref id="B47"><label>47.</label><mixed-citation>Cruceriu, D.; Baldasici, O.; Balacescu, O.; Berindan-Neagoe, I. The dual role of tumor necrosis factor-alpha (TNF-α) in breast cancer: Molecular insights and therapeutic approaches. Cell Oncol., 2020, 43(1), 1-18. doi: 10.1007/s13402-019-00489-1 PMID: 31900901</mixed-citation></ref><ref id="B48"><label>48.</label><mixed-citation>Hao, J.; Zhang, W.; Huang, Z. Bupivacaine modulates the apoptosis and ferroptosis in bladder cancer via phosphatidylinositol 3-kinase (PI3K)/AKT pathway. Bioengineered, 2022, 13(3), 6794-6806. doi: 10.1080/21655979.2022.2036909 PMID: 35246010</mixed-citation></ref><ref id="B49"><label>49.</label><mixed-citation>Yang, G.; Li, Z.; Dong, L.; Zhou, F. lncRNA ADAMTS9-AS1 promotes bladder cancer cell invasion, migration, and inhibits apoptosis and autophagy through PI3K/AKT/mTOR signaling pathway. Int. J. Biochem. Cell Biol., 2021, 140, 106069. doi: 10.1016/j.biocel.2021.106069 PMID: 34428588</mixed-citation></ref><ref id="B50"><label>50.</label><mixed-citation>Chi, M.; Liu, J.; Mei, C.; Shi, Y.; Liu, N.; Jiang, X.; Liu, C.; Xue, N.; Hong, H.; Xie, J.; Sun, X.; Yin, B.; Meng, X.; Wang, B. TEAD4 functions as a prognostic biomarker and triggers EMT via PI3K/AKT pathway in bladder cancer. J. Exp. Clin. Cancer Res., 2022, 41(1), 175. doi: 10.1186/s13046-022-02377-3 PMID: 35581606</mixed-citation></ref><ref id="B51"><label>51.</label><mixed-citation>Gourisankar, S.; Krokhotin, A.; Ji, W.; Liu, X.; Chang, C.Y.; Kim, S.H.; Li, Z.; Wenderski, W.; Simanauskaite, J.M.; Yang, H.; Vogel, H.; Zhang, T.; Green, M.R.; Gray, N.S.; Crabtree, G.R. Rewiring cancer drivers to activate apoptosis. Nature, 2023, 620(7973), 417-425. doi: 10.1038/s41586-023-06348-2 PMID: 37495688</mixed-citation></ref><ref id="B52"><label>52.</label><mixed-citation>Jia, X.; Wen, Z.; Sun, Q.; Zhao, X.; Yang, H.; Shi, X.; Xin, T. Apatinib suppresses the proliferation and apoptosis of gastric cancer cells via the PI3K/Akt signaling pathway. J. BUON, 2019, 24(5), 1985-1991. PMID: 31786865</mixed-citation></ref></ref-list></back></article>
