Abstract
Aim: To provide new methods and ideas for the clinical application of integrated traditional Chinese and Western medicine in the treatment of esophageal cancer.
Background: Traditional Chinese medicine compound Kushen injection (CKI) has been widely used in the clinic with adjuvant radiotherapy and chemotherapy. However, the mechanism of action of CKI as adjuvant therapy for esophageal cancer has not yet been described.
Methods: This study is based on network pharmacology, data mining, and molecular docking technology to explore the mechanism of action of CKI in the treatment of esophageal cancer. We obtained the effective ingredients and targets of CKI from the traditional Chinese medicine system pharmacology database and analysis platform (TCMSP) and esophageal cancer-related genes from the Online Mendelian Inheritance in Man (OMIM) and GeneCards databases.
Results: CKI mainly contains 58 active components. Among them, the top 5 active ingredients are quercetin, luteolin, naringenin, formononetin, and beta-sitostero. The target protein of the active ingredient was matched with the genes associated with esophageal cancer. The active ingredients targeted 187 esophageal cancer target proteins, including AKT1, MAPK1, MAPK3, TP53, HSP90AA1, and other proteins. Then, we enriched and analyzed the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) and used AutoDockVina to dock the core targets and compounds. Finally, PyMOL and Ligplot were used for data visualization.
Conclusion: This study provides a new method and ideas for the clinical application of integrated traditional Chinese and Western medicine in the treatment of esophageal cancer.
[1]
Wong, M.C.S.; Hamilton, W.; Whiteman, D.C.; Jiang, J.Y.; Qiao, Y.; Fung, F.D.H.; Wang, H.H.X.; Chiu, P.W.Y.; Ng, E.K.W.; Wu, J.C.Y.; Yu, J.; Chan, F.K.L.; Sung, J.J.Y. Global incidence and mortality of oesophageal cancer and their correlation with socioeconomic indicators temporal patterns and trends in 41 countries. Sci. Rep., 2018, 8(1), 4522.
[http://dx.doi.org/10.1038/s41598-018-19819-8] [PMID: 29540708]
[http://dx.doi.org/10.1038/s41598-018-19819-8] [PMID: 29540708]
[2]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[3]
Xu, W.; Lin, H.; Zhang, Y.; Chen, X.; Hua, B.; Hou, W.; Qi, X.; Pei, Y.; Zhu, X.; Zhao, Z.; Yang, L. Compound kushen injection suppresses human breast cancer stem-like cells by down-regulating the canonical Wnt/β-catenin pathway. J. Exp. Clin. Cancer Res., 2011, 30(1), 103.
[http://dx.doi.org/10.1186/1756-9966-30-103] [PMID: 22032476]
[http://dx.doi.org/10.1186/1756-9966-30-103] [PMID: 22032476]
[4]
Cui, J.; Qu, Z.; Harata-Lee, Y.; Nwe Aung, T.; Shen, H.; Wang, W.; Adelson, D.L. Cell cycle, energy metabolism and dna repair pathways in cancer cells are suppressed by compound kushen injection. BMC Cancer, 2019, 19(1), 103.
[http://dx.doi.org/10.1186/s12885-018-5230-8] [PMID: 30678652]
[http://dx.doi.org/10.1186/s12885-018-5230-8] [PMID: 30678652]
[5]
Wang, H.; Hu, H.; Rong, H.; Zhao, X. Effects of compound kushen injection on pathology and angiogenesis of tumor tissues. Oncol. Lett., 2018, 17(2), 2278-2282.
[http://dx.doi.org/10.3892/ol.2018.9861] [PMID: 30719109]
[http://dx.doi.org/10.3892/ol.2018.9861] [PMID: 30719109]
[6]
Nourmohammadi, S.; Aung, T.N.; Cui, J.; Pei, J.V.; De Ieso, M.L.; Harata-Lee, Y.; Qu, Z.; Adelson, D.L.; Yool, A.J. Effect of compound kushen injection, a natural compound mixture, and its identified chemical components on migration and invasion of colon, brain, and breast cancer cell lines. Front. Oncol., 2019, 9, 314.
[http://dx.doi.org/10.3389/fonc.2019.00314] [PMID: 31106149]
[http://dx.doi.org/10.3389/fonc.2019.00314] [PMID: 31106149]
[7]
Wang, W.; You, R.; Qin, W.; Hai, L.; Fang, M.; Huang, G.; Kang, R.; Li, M.; Qiao, Y.; Li, J.; Li, A. Anti-tumor activities of active ingredients in compound kushen injection. Acta Pharmacol. Sin., 2015, 36(6), 676-679.
[http://dx.doi.org/10.1038/aps.2015.24] [PMID: 25982630]
[http://dx.doi.org/10.1038/aps.2015.24] [PMID: 25982630]
[8]
Liu, X.S.; Jiang, J. Molecular mechanism of matrine-induced apoptosis in leukemia K562 cells. Am. J. Chin. Med., 2006, 34(6), 1095-1103.
[http://dx.doi.org/10.1142/S0192415X06004557] [PMID: 17163597]
[http://dx.doi.org/10.1142/S0192415X06004557] [PMID: 17163597]
[9]
Zhao, Z.; Fan, H.; Higgins, T.; Qi, J.; Haines, D.; Trivett, A.; Oppenheim, J.J.; Wei, H.; Li, J.; Lin, H.; Howard, O.M.Z. Fufang kushen injection inhibits sarcoma growth and tumor-induced hyperalgesia via TRPV1 signaling pathways. Cancer Lett., 2014, 355(2), 232-241.
[http://dx.doi.org/10.1016/j.canlet.2014.08.037] [PMID: 25242356]
[http://dx.doi.org/10.1016/j.canlet.2014.08.037] [PMID: 25242356]
[10]
Ao, M.; Xiao, X.; Li, Q. Efficacy and safety of compound kushen injection combined with chemotherapy on postoperative patients with breast cancer. Medicine, 2019, 98(3), e14024.
[http://dx.doi.org/10.1097/MD.0000000000014024] [PMID: 30653109]
[http://dx.doi.org/10.1097/MD.0000000000014024] [PMID: 30653109]
[11]
Zhang, D.; Ni, M.; Wu, J.; Liu, S.; Meng, Z.; Tian, J.; Zhang, X.; Zhang, B. The optimal Chinese herbal injections for use with radiotherapy to treat esophageal cancer: A systematic review and bayesian network meta-analysis. Front. Pharmacol., 2019, 9, 1470.
[http://dx.doi.org/10.3389/fphar.2018.01470] [PMID: 30662402]
[http://dx.doi.org/10.3389/fphar.2018.01470] [PMID: 30662402]
[12]
Shao, Q. The recent effect of radiotherapy combined with compound kushen injection for esophageal cancer. Radiother. Oncol., 2011, 99, S372-S373.
[http://dx.doi.org/10.1016/S0167-8140(11)71109-4]
[http://dx.doi.org/10.1016/S0167-8140(11)71109-4]
[13]
Fang, J.; Wang, L.; Wu, T.; Yang, C.; Gao, L.; Cai, H.; Liu, J.; Fang, S.; Chen, Y.; Tan, W.; Wang, Q. Network pharmacology-based study on the mechanism of action for herbal medicines in Alzheimer treatment. J. Ethnopharmacol., 2017, 196, 281-292.
[http://dx.doi.org/10.1016/j.jep.2016.11.034] [PMID: 27888133]
[http://dx.doi.org/10.1016/j.jep.2016.11.034] [PMID: 27888133]
[14]
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.
[http://dx.doi.org/10.1186/1758-2946-6-13] [PMID: 24735618]
[http://dx.doi.org/10.1186/1758-2946-6-13] [PMID: 24735618]
[15]
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.
[http://dx.doi.org/10.1093/nar/gkaa1100] [PMID: 33237286]
[http://dx.doi.org/10.1093/nar/gkaa1100] [PMID: 33237286]
[16]
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.
[http://dx.doi.org/10.1093/nar/gky1151] [PMID: 30445645]
[http://dx.doi.org/10.1093/nar/gky1151] [PMID: 30445645]
[17]
Stelzer, G.; Rosen, N.; Plaschkes, I.; Zimmerman, S.; Twik, M.; Fishilevich, S.; Stein, T. I.; Nudel, R.; Lieder, I.; Mazor, Y.; Kaplan, S.; Dahary, D.; Warshawsky, D.; Guan-Golan, Y.; Kohn, A.; Rappaport, N.; Safran, M.; Lancet, D. The genecards suite: From gene data mining to disease genome sequence analyses. Curr. Protoc. Bioinformatics, 2016, 54, 1.30.1-1.30.33.
[http://dx.doi.org/10.1002/cpbi.5]
[http://dx.doi.org/10.1002/cpbi.5]
[18]
Szklarczyk, D.; Gable, A.L.; Lyon, D.; Junge, A.; Wyder, S.; Huerta-Cepas, J.; Simonovic, M.; Doncheva, N.T.; Morris, J.H.; Bork, P.; Jensen, L.J.; Mering, C. STRING v11: Protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res., 2019, 47(D1), D607-D613.
[http://dx.doi.org/10.1093/nar/gky1131] [PMID: 30476243]
[http://dx.doi.org/10.1093/nar/gky1131] [PMID: 30476243]
[19]
Burley, S.K.; Berman, H.M.; Bhikadiya, C.; Bi, C.; Chen, L.; Costanzo, L.D.; Christie, C.; Duarte, J.M.; Dutta, S.; Feng, Z.; Ghosh, S.; Goodsell, D.S.; Green, R.K.; Guranovic, V.; Guzenko, D.; Hudson, B.P.; Liang, Y.; Lowe, R.; Peisach, E.; Periskova, I.; Randle, C.; Rose, A.; Sekharan, M.; Shao, C.; Tao, Y-P.; Valasatava, Y.; Voigt, M.; Westbrook, J.; Young, J.; Zardecki, C.; Zhuravleva, M.; Kurisu, G.; Nakamura, H.; Kengaku, Y.; Cho, H.; Sato, J.; Kim, J.Y.; Ikegawa, Y.; Nakagawa, A.; Yamashita, R.; Kudou, T.; Bekker, G-J.; Suzuki, H.; Iwata, T.; Yokochi, M.; Kobayashi, N.; Fujiwara, T.; Velankar, S.; Kleywegt, G.J.; Anyango, S.; Armstrong, D.R.; Berrisford, J.M.; Conroy, M.J.; Dana, J.M.; Deshpande, M.; Gane, P.; Gáborová, R.; Gupta, D.; Gutmanas, A. Koča, J.; Mak, L.; Mir, S.; Mukhopadhyay, A.; Nadzirin, N.; Nair, S.; Patwardhan, A.; Paysan-Lafosse, T.; Pravda, L.; Salih, O.; Sehnal, D.; Varadi, M.; Vařeková, R.; Markley, J.L.; Hoch, J.C.; Romero, P.R.; Baskaran, K.; Maziuk, D.; Ulrich, E.L.; Wedell, J.R.; Yao, H.; Livny, M.; Ioannidis, Y.E. Protein data bank: The single global archive for 3d macromolecular structure data. Nucleic Acids Res., 2019, 47(D1), D520-D528.
[http://dx.doi.org/10.1093/nar/gky949] [PMID: 30357364]
[http://dx.doi.org/10.1093/nar/gky949] [PMID: 30357364]
[20]
Guo, D.; Jin, J.; Liu, J.; Wang, Y.; Li, D.; He, Y. Baicalein inhibits the progression and promotes radiosensitivity of esophageal squamous cell carcinoma by targeting HIF-1A. Drug Des. Devel. Ther., 2022, 16, 2423-2436.
[http://dx.doi.org/10.2147/DDDT.S370114] [PMID: 35937565]
[http://dx.doi.org/10.2147/DDDT.S370114] [PMID: 35937565]
[21]
Hsin, K.Y.; Ghosh, S.; Kitano, H. Combining machine learning systems and multiple docking simulation packages to improve docking prediction reliability for network pharmacology. PLoS One, 2013, 8(12), e83922.
[http://dx.doi.org/10.1371/journal.pone.0083922] [PMID: 24391846]
[http://dx.doi.org/10.1371/journal.pone.0083922] [PMID: 24391846]
[22]
Wang, T.; Li, Q.; Bi, K. Bioactive flavonoids in medicinal plants: Structure, activity and biological fate. Asian J. Pharm. Sci., 2018, 13(1), 12-23.
[http://dx.doi.org/10.1016/j.ajps.2017.08.004] [PMID: 32104374]
[http://dx.doi.org/10.1016/j.ajps.2017.08.004] [PMID: 32104374]
[23]
Lin, Y.; Yngve, A.; Lagergren, J.; Lu, Y. A dietary pattern rich in lignans, quercetin and resveratrol decreases the risk of oesophageal cancer. Br. J. Nutr., 2014, 112(12), 2002-2009.
[http://dx.doi.org/10.1017/S0007114514003055] [PMID: 25345471]
[http://dx.doi.org/10.1017/S0007114514003055] [PMID: 25345471]
[24]
Davoodvandi, A.; Shabani, V.M.; Clark, C.C.T.; Jafarnejad, S. Quercetin as an anticancer agent: Focus on esophageal cancer. J. Food Biochem., 2020, 44(9), e13374.
[http://dx.doi.org/10.1111/jfbc.13374] [PMID: 32686158]
[http://dx.doi.org/10.1111/jfbc.13374] [PMID: 32686158]
[25]
Wang, T.T.; Wang, S.K.; Huang, G.L.; Sun, G.J. Luteolin induced-growth inhibition and apoptosis of human esophageal squamous carcinoma cell line Eca109 cells in vitro. Asian Pac. J. Cancer Prev., 2012, 13(11), 5455-5461.
[http://dx.doi.org/10.7314/APJCP.2012.13.11.5455] [PMID: 23317200]
[http://dx.doi.org/10.7314/APJCP.2012.13.11.5455] [PMID: 23317200]
[26]
Chen, P.; Zhang, J.Y.; Sha, B.B.; Ma, Y.E.; Hu, T.; Ma, Y.C.; Sun, H.; Shi, J.X.; Dong, Z.M.; Li, P. Luteolin inhibits cell proliferation and induces cell apoptosis via down-regulation of mitochondrial membrane potential in esophageal carcinoma cells EC1 and KYSE450. Oncotarget, 2017, 8(16), 27471-27480.
[http://dx.doi.org/10.18632/oncotarget.15832] [PMID: 28460467]
[http://dx.doi.org/10.18632/oncotarget.15832] [PMID: 28460467]
[27]
Liu, Z.C.; Cao, K.; Xiao, Z.H.; Qiao, L.; Wang, X.Q.; Shang, B.; Jia, Y.; Wang, Z. VRK1 promotes cisplatin resistance by up-regulating c-MYC via c-Jun activation and serves as a therapeutic target in esophageal squamous cell carcinoma. Oncotarget, 2017, 8(39), 65642-65658.
[http://dx.doi.org/10.18632/oncotarget.20020] [PMID: 29029460]
[http://dx.doi.org/10.18632/oncotarget.20020] [PMID: 29029460]
[28]
Zhao, Z.; Jin, G.; Ge, Y.; Guo, Z. Naringenin inhibits migration of breast cancer cells via inflammatory and apoptosis cell signaling pathways. Inflammopharmacology, 2019, 27(5), 1021-1036.
[http://dx.doi.org/10.1007/s10787-018-00556-3] [PMID: 30941613]
[http://dx.doi.org/10.1007/s10787-018-00556-3] [PMID: 30941613]
[29]
Tan, Z.; Sun, Y.; Liu, M.; Xia, L.; Cao, F.; Qi, Y.; Song, Y. Retracted: Naringenin inhibits cell migration, invasion, and tumor growth by regulating circFOXM1/miR-3619-5p/SPAG5 axis in lung cancer. Cancer Biother. Radiopharm., 2020, 35(10), e826-e838.
[http://dx.doi.org/10.1089/cbr.2019.3520] [PMID: 32598178]
[http://dx.doi.org/10.1089/cbr.2019.3520] [PMID: 32598178]
[30]
Ong, S.; Shanmugam, M.; Fan, L.; Fraser, S.; Arfuso, F.; Ahn, K.; Sethi, G.; Bishayee, A. Focus on formononetin: Anticancer potential and molecular targets. Cancers, 2019, 11(5), 611.
[http://dx.doi.org/10.3390/cancers11050611] [PMID: 31052435]
[http://dx.doi.org/10.3390/cancers11050611] [PMID: 31052435]
[31]
Lee, S.; Rauch, J.; Kolch, W. Targeting MAPK signaling in cancer: Mechanisms of drug resistance and sensitivity. Int. J. Mol. Sci., 2020, 21(3), 1102.
[http://dx.doi.org/10.3390/ijms21031102] [PMID: 32046099]
[http://dx.doi.org/10.3390/ijms21031102] [PMID: 32046099]
[32]
Slack, C. Ras signaling in aging and metabolic regulation. Nutr. Healthy Aging, 2017, 4(3), 195-205.
[http://dx.doi.org/10.3233/NHA-160021] [PMID: 29276789]
[http://dx.doi.org/10.3233/NHA-160021] [PMID: 29276789]
[33]
Ong, C.S.; Zhou, J.; Ong, C.N.; Shen, H.M. Luteolin induces G1 arrest in human nasopharyngeal carcinoma cells via the Akt-GSK-3β-Cyclin D1 pathway. Cancer Lett., 2010, 298(2), 167-175.
[http://dx.doi.org/10.1016/j.canlet.2010.07.001] [PMID: 20655656]
[http://dx.doi.org/10.1016/j.canlet.2010.07.001] [PMID: 20655656]
[34]
Wang, X.; Li, M.; Hu, M.; Wei, P.; Zhu, W. BAMBI overexpression together with β-sitosterol ameliorates NSCLC via inhibiting autophagy and inactivating TGF-β/Smad2/3 pathway. Oncol. Rep., 2017, 37(5), 3046-3054.
[http://dx.doi.org/10.3892/or.2017.5508] [PMID: 28440452]
[http://dx.doi.org/10.3892/or.2017.5508] [PMID: 28440452]
[35]
Vundru, S.S. Kale, R.K.; Singh, R.P. β-sitosterol induces G1 arrest and causes depolarization of mitochondrial membrane potential in breast carcinoma MDA-MB-231 cells. BMC Complement. Altern. Med., 2013, 13(1), 280.
[http://dx.doi.org/10.1186/1472-6882-13-280] [PMID: 24160369]
[http://dx.doi.org/10.1186/1472-6882-13-280] [PMID: 24160369]
[36]
Park, S.; Bazer, F.W.; Lim, W.; Song, G. The O-methylated isoflavone, formononetin, inhibits human ovarian cancer cell proliferation by sub G0/G1 cell phase arrest through PI3K/AKT and ERK1/2 inactivation. J. Cell. Biochem., 2018, 119(9), 7377-7387.
[http://dx.doi.org/10.1002/jcb.27041] [PMID: 29761845]
[http://dx.doi.org/10.1002/jcb.27041] [PMID: 29761845]
[37]
Nguyen, T.T.T.; Tran, E.; Nguyen, T.H.; Do, P.T.; Huynh, T.H.; Huynh, H. The role of activated MEK-ERK pathway in quercetin-induced growth inhibition and apoptosis in A549 lung cancer cells. Carcinogenesis, 2003, 25(5), 647-659.
[http://dx.doi.org/10.1093/carcin/bgh052] [PMID: 14688022]
[http://dx.doi.org/10.1093/carcin/bgh052] [PMID: 14688022]
[38]
Granado-Serrano, A.B.; Martín, M.A.; Bravo, L.; Goya, L.; Ramos, S. Quercetin induces apoptosis via caspase activation, regulation of Bcl-2, and inhibition of PI-3-kinase/Akt and ERK pathways in a human hepatoma cell line (HepG2). J. Nutr., 2006, 136(11), 2715-2721.
[http://dx.doi.org/10.1093/jn/136.11.2715] [PMID: 17056790]
[http://dx.doi.org/10.1093/jn/136.11.2715] [PMID: 17056790]
[39]
Im, E.; Yeo, C.; Lee, E.O. Luteolin induces caspase-dependent apoptosis via inhibiting the AKT/osteopontin pathway in human hepatocellular carcinoma SK-Hep-1 cells. Life Sci., 2018, 209, 259-266.
[http://dx.doi.org/10.1016/j.lfs.2018.08.025] [PMID: 30107166]
[http://dx.doi.org/10.1016/j.lfs.2018.08.025] [PMID: 30107166]
[40]
Li, H.; Tan, L.; Zhang, J.W.; Chen, H.; Liang, B.; Qiu, T.; Li, Q.S.; Cai, M.; Zhang, Q.H. Quercetin is the active component of yang-yin-qing-fei-tang to induce apoptosis in non-small cell lung cancer. Am. J. Chin. Med., 2019, 47(4), 879-893.
[http://dx.doi.org/10.1142/S0192415X19500460] [PMID: 31179723]
[http://dx.doi.org/10.1142/S0192415X19500460] [PMID: 31179723]
[41]
Zhao, Y.; Chang, S.K.C.; Qu, G.; Li, T.; Cui, H. Beta-sitosterol inhibits cell growth and induces apoptosis in SGC-7901 human stomach cancer cells. J. Agric. Food Chem., 2009, 57(12), 5211-5218.
[http://dx.doi.org/10.1021/jf803878n] [PMID: 19456133]
[http://dx.doi.org/10.1021/jf803878n] [PMID: 19456133]
[42]
von Holtz, R.L. Fink, C.S.; Awad, A.B. β-sitosterol activates the sphingomyelin cycle and induces apoptosis in LNCaP human prostate cancer cells. Nutr. Cancer, 1998, 32(1), 8-12.
[http://dx.doi.org/10.1080/01635589809514709] [PMID: 9824850]
[http://dx.doi.org/10.1080/01635589809514709] [PMID: 9824850]
[43]
Yu, D.; Ye, T.; Xiang, Y.; Shi, Z.; Zhang, J.; Lou, B.; Zhang, F.; Chen, B.; Zhou, M. Quercetin inhibits epithelial–mesenchymal transition, decreases invasiveness and metastasis, and reverses IL-6 induced epithelial-mesenchymal transition, expression of MMP by inhibiting STAT3 signaling in pancreatic cancer cells. OncoTargets Ther., 2017, 10, 4719-4729.
[http://dx.doi.org/10.2147/OTT.S136840] [PMID: 29026320]
[http://dx.doi.org/10.2147/OTT.S136840] [PMID: 29026320]
[44]
Zhang, J.; Liu, L.; Wang, J.; Ren, B.; Zhang, L.; Li, W. Formononetin, an isoflavone from astragalus membranaceus inhibits proliferation and metastasis of ovarian cancer cells. J. Ethnopharmacol., 2018, 221, 91-99.
[http://dx.doi.org/10.1016/j.jep.2018.04.014] [PMID: 29660466]
[http://dx.doi.org/10.1016/j.jep.2018.04.014] [PMID: 29660466]
[45]
Debele, T.A.; Mekuria, S.L.; Tsai, H.C. Synthesis and characterization of redox-sensitive heparin-β-sitosterol micelles: Their application as carriers for the pharmaceutical agent, doxorubicin, and investigation of their antimetastatic activities in vitro. Mater. Sci. Eng. C, 2017, 75, 1326-1338.
[http://dx.doi.org/10.1016/j.msec.2017.03.052] [PMID: 28415422]
[http://dx.doi.org/10.1016/j.msec.2017.03.052] [PMID: 28415422]
[46]
Gendrisch, F.; Esser, P.R.; Schempp, C.M.; Wölfle, U. Luteolin as a modulator of skin aging and inflammation. Biofactors, 2021, 47(2), 170-180.
[http://dx.doi.org/10.1002/biof.1699] [PMID: 33368702]
[http://dx.doi.org/10.1002/biof.1699] [PMID: 33368702]
[47]
Avila-Carrasco, L.; Majano, P.; Sánchez-Toméro, J.A.; Selgas, R.; López-Cabrera, M.; Aguilera, A.; González Mateo, G. Natural plants compounds as modulators of epithelial-to-mesenchymal transition. Front. Pharmacol., 2019, 10, 715.
[http://dx.doi.org/10.3389/fphar.2019.00715] [PMID: 31417401]
[http://dx.doi.org/10.3389/fphar.2019.00715] [PMID: 31417401]
[48]
Tseng, P.L.; Chen, C.W.; Hu, K.H.; Cheng, H.C.; Lin, Y.H.; Tsai, W.H.; Cheng, T.J.; Wu, W.H.; Yeh, C.W.; Lin, C.C.; Tsai, H.J.; Chang, H.C.; Chuang, J.H.; Shan, Y.S.; Chang, W.T. The decrease of glycolytic enzyme hexokinase 1 accelerates tumor malignancy via deregulating energy metabolism but sensitizes cancer cells to 2-deoxyglucose inhibition. Oncotarget, 2018, 9(27), 18949-18969.
[http://dx.doi.org/10.18632/oncotarget.24855] [PMID: 29721175]
[http://dx.doi.org/10.18632/oncotarget.24855] [PMID: 29721175]
[49]
Wu, H.; Pan, L.; Gao, C.; Xu, H.; Li, Y.; Zhang, L.; Ma, L.; Meng, L.; Sun, X.; Qin, H. Quercetin inhibits the proliferation of glycolysis-addicted HCC cells by reducing hexokinase 2 and Akt-mTOR pathway. Molecules, 2019, 24(10), 1993.
[http://dx.doi.org/10.3390/molecules24101993] [PMID: 31137633]
[http://dx.doi.org/10.3390/molecules24101993] [PMID: 31137633]
[50]
Palombo, R.; Caporali, S.; Falconi, M.; Iacovelli, F.; Morozzo, D.R.B.; Lo Surdo, A.; Campione, E.; Candi, E.; Melino, G.; Bernardini, S.; Terrinoni, A. Luteolin-7-O-β-d-glucoside inhibits cellular energy production interacting with hek2 in keratinocytes. Int. J. Mol. Sci., 2019, 20(11), 2689.
[http://dx.doi.org/10.3390/ijms20112689] [PMID: 31159225]
[http://dx.doi.org/10.3390/ijms20112689] [PMID: 31159225]
[51]
Nagao, A.; Kobayashi, M.; Koyasu, S.; Chow, C.C.T.; Harada, H. HIF-1-dependent reprogramming of glucose metabolic pathway of cancer cells and its therapeutic significance. Int. J. Mol. Sci., 2019, 20(2), 238.
[http://dx.doi.org/10.3390/ijms20020238] [PMID: 30634433]
[http://dx.doi.org/10.3390/ijms20020238] [PMID: 30634433]
[52]
Vaupel, P.; Mayer, A. Hypoxia in tumors: Pathogenesis-related classification, characterization of hypoxia subtypes, and associated biological and clinical implications. Adv. Exp. Med. Biol., 2014, 812, 19-24.
[http://dx.doi.org/10.1007/978-1-4939-0620-8_3] [PMID: 24729210]
[http://dx.doi.org/10.1007/978-1-4939-0620-8_3] [PMID: 24729210]
[53]
Ansó, E.; Zuazo, A.; Irigoyen, M.; Urdaci, M.C.; Rouzaut, A.; Martínez-Irujo, J.J. Flavonoids inhibit hypoxia-induced vascular endothelial growth factor expression by a HIF-1 independent mechanism. Biochem. Pharmacol., 2010, 79(11), 1600-1609.
[http://dx.doi.org/10.1016/j.bcp.2010.02.004] [PMID: 20153296]
[http://dx.doi.org/10.1016/j.bcp.2010.02.004] [PMID: 20153296]
[54]
Kim, A.H.; Khursigara, G.; Sun, X.; Franke, T.F.; Chao, M.V. Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol. Cell. Biol., 2001, 21(3), 893-901.
[http://dx.doi.org/10.1128/MCB.21.3.893-901.2001] [PMID: 11154276]
[http://dx.doi.org/10.1128/MCB.21.3.893-901.2001] [PMID: 11154276]
[55]
Du, K.; Montminy, M. CREB is a regulatory target for the protein kinase Akt/PKB. J. Biol. Chem., 1998, 273(49), 32377-32379.
[http://dx.doi.org/10.1074/jbc.273.49.32377] [PMID: 9829964]
[http://dx.doi.org/10.1074/jbc.273.49.32377] [PMID: 9829964]
[56]
Chin, Y.R.; Toker, A. The actin-bundling protein palladin is an Akt1-specific substrate that regulates breast cancer cell migration. Mol. Cell, 2010, 38(3), 333-344.
[http://dx.doi.org/10.1016/j.molcel.2010.02.031] [PMID: 20471940]
[http://dx.doi.org/10.1016/j.molcel.2010.02.031] [PMID: 20471940]
