Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

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

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Aesculetin Inhibits Proliferation and Induces Mitochondrial Apoptosis in Bladder Cancer Cells by Suppressing the MEK/ERK Signaling Pathway

Author(s): Li Han, Peiwu Li, Xu Fu, Zhenzhen Huang and Wen Yin*

Volume 23, Issue 4, 2023

Published on: 20 August, 2022

Page: [478 - 487] Pages: 10

DOI: 10.2174/1871520622666220615142636

Price: $65

conference banner
Abstract

Background: Aesculetin (AE), a natural coumarin derivative found in traditional medicinal herbs, has a variety of pharmacological effects. However, the role of AE and its molecular mechanisms of action on bladder cancer remains undefined.

Objective: The study aims to explore the anti-tumor effects of AE on bladder cancer cells and the associated molecular mechanisms.

Methods: We performed a Cell Counting Kit-8 assay to examine the inhibitory effects of AE on 5637 and T24 cells. The anti-tumor effects of AE on 5637 cells were evaluated by performing colony formation, living/dead cell staining, apoptosis, cell cycle, migration and invasion assays. The expression levels of related proteins were determined using western blotting.

Results: The viability of 5637 and T24 cells was decreased by AE. AE significantly inhibited colony formation, arrested the cell cycle at the G0/G1 phase, decreased migration and invasion, decreased the mitochondrial membrane potential and increased apoptosis in 5637 cells. Western blotting results showed the release of cytochrome C from mitochondria; the activation of caspase-9 and caspase-3; decrease in CDK4, CCND1, MMP2 and MMP9 levels and an increase in the BAX/BCL-2 protein ratio after treatment with AE. AE also downregulated the levels of p-ERK and p- MEK proteins. Pre-treatment with U0126 significantly enhanced the anti-tumor effects of AE.

Conclusions: AE inhibited the proliferation and induced the apoptosis of bladder cancer cells through the MEK/ERK pathway. These findings provide possible therapeutic strategies for bladder cancer.

Keywords: bladder cancer, Aesculetin, MEK/ERK, proliferation, apoptosis, migration and invasion

« Previous
Graphical Abstract

[1]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of inci-dence 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]
[2]
Babjuk, M.; Burger, M.; Compérat, E.M.; Gontero, P.; Mostafid, A.H.; Palou, J.; van Rhijn, B.W.G.; Rouprêt, M.; Shariat, S.F.; Sylvester, R.; Zigeuner, R.; Capoun, O.; Cohen, D.; Escrig, J.L.D.; Hernández, V.; Peyronnet, B.; Seisen, T.; Soukup, V. European association of urology guidelines on non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ) - 2019 update. Eur. Urol., 2019, 76(5), 639-657.
[http://dx.doi.org/10.1016/j.eururo.2019.08.016] [PMID: 31443960]
[3]
Mylonas, K.S.; O.M, Ziogas; EL, Kabab; Nasioudis, D. Malignant urachal neoplasms: A population-based study and systematic review of literature. Urol. Oncol, 2017, 35(1), 33 e11-33 e19.
[4]
Sauter, E.R. Cancer prevention and treatment using combination therapy with natural compounds. Expert Rev. Clin. Pharmacol., 2020, 13(3), 265-285.
[http://dx.doi.org/10.1080/17512433.2020.1738218] [PMID: 32154753]
[5]
Bishayee, A.; Sethi, G. Bioactive natural products in cancer prevention and therapy: Progress and promise. Semin. Cancer Biol., 2016, 40-41, 1-3.
[http://dx.doi.org/10.1016/j.semcancer.2016.08.006] [PMID: 27565447]
[6]
Oh, S.Y.; Kim, Y.H.; Kang, M.K.; Lee, E.J.; Kim, D.Y.; Oh, H.; Kim, S.I.; Na, W.; Kang, Y.H. Aesculetin attenuates alveolar injury and fibrosis induced by close contact of alveolar epithelial cells with blood-derived macrophages via IL-8 signaling. Int. J. Mol. Sci., 2020, 21(15), E5518.
[http://dx.doi.org/10.3390/ijms21155518] [PMID: 32752252]
[7]
He, Y.; Li, C.; Ma, Q.; Chen, S. Esculetin inhibits oxidative stress and apoptosis in H9c2 cardiomyocytes following hypox-ia/reoxygenation injury. Biochem. Biophys. Res. Commun., 2018, 501(1), 139-144.
[http://dx.doi.org/10.1016/j.bbrc.2018.04.195] [PMID: 29705703]
[8]
Na, W.; Lee, E.J.; Kang, M.K.; Kim, Y.H.; Kim, D.Y.; Oh, H.; Kim, S.I.; Oh, S.Y.; Kang, Y.H. Aesculetin inhibits osteoclastic bone resorp-tion through blocking ruffled border formation and Lysosomal trafficking. Int. J. Mol. Sci., 2020, 21(22), E8581.
[http://dx.doi.org/10.3390/ijms21228581] [PMID: 33203061]
[9]
Chang, H.T.; Chou, C.T.; Lin, Y.S.; Shieh, P.; Kuo, D.H.; Jan, C.R.; Liang, W.Z. Esculetin, a natural coumarin compound, evokes Ca2+ movement and activation of Ca2+-associated mitochondrial apoptotic pathways that involved cell cycle arrest in ZR-75-1 human breast cancer cells. Tumour Biol., 2016, 37(4), 4665-4678.
[http://dx.doi.org/10.1007/s13277-015-4286-1] [PMID: 26508031]
[10]
Wang, G.; Lu, M.; Yao, Y.; Wang, J.; Li, J. Esculetin exerts antitumor effect on human gastric cancer cells through IGF-1/PI3K/Akt signal-ing pathway. Eur. J. Pharmacol., 2017, 814, 207-215.
[http://dx.doi.org/10.1016/j.ejphar.2017.08.025] [PMID: 28847482]
[11]
Lee, R.H.; Jeon, Y.J.; Cho, J.H.; Jang, J.Y.; Kong, I.K.; Kim, S.H.; Kim, M.S.; Chung, H.J.; Oh, K.B.; Park, S.M.; Shin, J.C.; Seo, J.M.; Ko, S.; Shim, J.H.; Chae, J.I. Esculetin exerts anti-proliferative effects against non-small-cell lung carcinoma by suppressing specificity protein 1 in vitro. Gen. Physiol. Biophys., 2017, 36(1), 31-39.
[http://dx.doi.org/10.4149/gpb_2016024] [PMID: 27901471]
[12]
Yan, L.; Yu, H.H.; Liu, Y.S.; Wang, Y.S.; Zhao, W.H. Esculetin enhances the inhibitory effect of 5-Fluorouracil on the proliferation, mi-gration and epithelial-mesenchymal transition of colorectal cancer. Cancer Biomark., 2019, 24(2), 231-240.
[http://dx.doi.org/10.3233/CBM-181764] [PMID: 30689555]
[13]
Arora, R.; Sawney, S.; Saini, V.; Steffi, C.; Tiwari, M.; Saluja, D. Esculetin induces antiproliferative and apoptotic response in pancreatic cancer cells by directly binding to KEAP1. Mol. Cancer, 2016, 15(1), 64.
[http://dx.doi.org/10.1186/s12943-016-0550-2] [PMID: 27756327]
[14]
Li, J.; Li, S.; Wang, X.; Wang, H. Esculetin induces apoptosis of SMMC-7721 cells through IGF-1/PI3K/Akt-mediated mitochondrial pathways. Can. J. Physiol. Pharmacol., 2017, 95(7), 787-794.
[http://dx.doi.org/10.1139/cjpp-2016-0548] [PMID: 28177662]
[15]
Rubio, V.; García-Pérez, A.I.; Herráez, A.; Diez, J.C. Different roles of Nrf2 and NFKB in the antioxidant imbalance produced by esculetin or quercetin on NB4 leukemia cells. Chem. Biol. Interact., 2018, 294, 158-166.
[http://dx.doi.org/10.1016/j.cbi.2018.08.015] [PMID: 30171828]
[16]
Yao, L.C.; Wu, L.; Wang, W.; Zhai, L.L.; Ye, L.; Xiang, F.; Tang, Z.G. Panax notoginseng Saponins promote cell death and chemosensi-tivity in pancreatic cancer through the apoptosis and autophagy pathways. Anticancer. Agents Med. Chem., 2021, 21(13), 1680-1688.
[http://dx.doi.org/10.2174/1871520620999201110191459] [PMID: 33176665]
[17]
Chen, C.; Zhao, Z.; Dong, Q.; Gao, X.; Xu, H.; Yang, R.; Qin, J.; Luo, D. Anti-tumor activity and underlying mechanism of phomoxantho-ne B in MCF7 cells. Anticancer. Agents Med. Chem., 2021, 21(14), 1825-1834.
[http://dx.doi.org/10.2174/1871520620999201124215511] [PMID: 33238849]
[18]
Li, G.; Qiao, K.; Xu, X.; Wang, C. Cepharanthine regulates autophagy via activating the p38 signaling pathway in lung adenocarcinoma cells. Anticancer. Agents Med. Chem., 2022, 22(8), 1523-1529.
[PMID: 34477532]
[19]
Liu, X.; Zhou, Z.; Wang, Y.; Zhu, K.; Deng, W.; Li, Y.; Zhou, X.; Chen, L.; Li, Y.; Xie, A.; Zeng, T.; Wang, G.; Fu, B. Corrigendum: Downregulation of HMGA1 mediates autophagy and inhibits migration and invasion in bladder cancer via miRNA-221/TP53INP1/p-ERK axis. Front. Oncol., 2020, 10, 1735.
[http://dx.doi.org/10.3389/fonc.2020.01735] [PMID: 33014857]
[20]
Zhao, T.C.; Liang, S.Y.; Zhou, Z.H.; Ju, W.T.; Zhang, Z.Y.; Zhu, D.W.; Zhong, L.P. Targeting ERK combined with apatinib may be a promising therapeutic strategy for treating oral squamous cell carcinoma. Am. J. Cancer Res., 2021, 11(6), 2960-2974.
[PMID: 34249438]
[21]
Coen, J.J.; Zhang, P.; Saylor, P.J.; Lee, C.T.; Wu, C.L.; Parker, W.; Lautenschlaeger, T.; Zietman, A.L.; Efstathiou, J.A.; Jani, A.B.; Kucuk, O.; Souhami, L.; Rodgers, J.P.; Sandler, H.M.; Shipley, W.U. Bladder preservation with twice-a-day radiation plus fluorouracil/cisplatin or once daily radiation plus gemcitabine for muscle-invasive bladder cancer: NRG/RTOG 0712-A randomized phase II trial. J. Clin. Oncol., 2019, 37(1), 44-51.
[http://dx.doi.org/10.1200/JCO.18.00537] [PMID: 30433852]
[22]
Campanario Pérez, R.; Campanario Pérez, F. Current treatment options and future perspectives on first line metastatic bladder cancer. Arch. Esp. Urol., 2020, 73(10), 996-1006.
[PMID: 33269718]
[23]
Phan, T.G.; Croucher, P.I. The dormant cancer cell life cycle. Nat. Rev. Cancer, 2020, 20(7), 398-411.
[http://dx.doi.org/10.1038/s41568-020-0263-0] [PMID: 32488200]
[24]
Sun, F.; Li, N.; Tong, X.; Zeng, J.; He, S.; Gai, T.; Bai, Y.; Liu, L.; Lu, K.; Shen, J.; Han, M.; Lu, C.; Dai, F. Ara-c induces cell cycle G1/S arrest by inducing upregulation of the INK4 family gene or directly inhibiting the formation of the cell cycle-dependent complex CDK4/cyclin D1. Cell Cycle, 2019, 18(18), 2293-2306.
[http://dx.doi.org/10.1080/15384101.2019.1644913] [PMID: 31322047]
[25]
Edathara, P.M.; Chintalapally, S.; Makani, V.K.K.; Pant, C.; Yerramsetty, S.D.; Rao, M.; Bhadra, M.P. Inhibitory role of oleanolic acid and esculetin in HeLa cells involve multiple signaling pathways. Gene, 2021, 771, 145370.
[http://dx.doi.org/10.1016/j.gene.2020.145370] [PMID: 33346097]
[26]
Zhang, J.; Feng, M.; Guan, W. Naturally occurring aesculetin coumarin exerts antiproliferative effects in gastric cancer cells mediated via apoptotic cell death, cell cycle arrest and targeting PI3K/AKT/M-TOR signalling pathway. Acta Biochim. Pol., 2021, 68(1), 109-113.
[http://dx.doi.org/10.18388/abp.2020_5463] [PMID: 33728889]
[27]
da Costa, N.M.M.; de Siqueira, A.S.; Ribeiro, A.L.R.; da Silva Kataoka, M.S.; Jaeger, R.G.; de Alves-Júnior, S.M.; Smith, A.M. de Jesus viana Pinheiro, J. Role of HIF-1α and CASPASE-3 in cystogenesis of odontogenic cysts and tumors. Clin. Oral Investig., 2018, 22(1), 141-149.
[http://dx.doi.org/10.1007/s00784-017-2090-6] [PMID: 28238093]
[28]
Wang, J.; Lu, M.L.; Dai, H.L.; Zhang, S.P.; Wang, H.X.; Wei, N. Esculetin, a coumarin derivative, exerts in vitro and in vivo antiprolifera-tive activity against hepatocellular carcinoma by initiating a mitochondrial-dependent apoptosis pathway. Braz. J. Med. Biol. Res., 2015, 48(3), 245-253.
[http://dx.doi.org/10.1590/1414-431x20144074] [PMID: 25517918]
[29]
Xiang, S.; Zhang, K.; Yang, G.; Gao, D.; Zeng, C.; He, M. Mitochondria-targeted and resveratrol-loaded dual-function titanium disulfide nanosheets for photothermal-triggered Tumor Chemotherapy. Nanoscale Res. Lett., 2019, 14(1), 211.
[http://dx.doi.org/10.1186/s11671-019-3044-5] [PMID: 31227943]
[30]
Ashrafizadeh, M.; Hushmandi, K.; Hashemi, M.; Akbari, M.E.; Kubatka, P.; Raei, M.; Koklesova, L.; Shahinozzaman, M.; Moham-madinejad, R.; Najafi, M.; Sethi, G.; Kumar, A.P.; Zarrabi, A. Role of microRNA/Epithelial-to-Mesenchymal transition axis in the metasta-sis of bladder cancer. Biomolecules, 2020, 10(8), E1159.
[http://dx.doi.org/10.3390/biom10081159] [PMID: 32784711]
[31]
Amar, S.; Smith, L.; Fields, G.B. Matrix metalloproteinase collagenolysis in health and disease. Biochim. Biophys. Acta Mol. Cell Res., 2017, 1864(11)(11 Pt A), 1940-1951.
[http://dx.doi.org/10.1016/j.bbamcr.2017.04.015] [PMID: 28456643]
[32]
Cabral-Pacheco, G.A.; Garza-Veloz, I.; Castruita-De la Rosa, C.; Ramirez-Acuña, J.M.; Perez-Romero, B.A.; Guerrero-Rodriguez, J.F.; Martinez-Avila, N.; Martinez-Fierro, M.L. The roles of matrix metalloproteinases and their inhibitors in human diseases. Int. J. Mol. Sci., 2020, 21(24), E9739.
[http://dx.doi.org/10.3390/ijms21249739] [PMID: 33419373]
[33]
Cheng, T.C.; Din, Z.H.; Su, J.H.; Wu, Y.J.; Liu, C.I. Sinulariolide suppresses cell migration and invasion by inhibiting matrix metallopro-teinase-2/-9 and urokinase through the PI3K/AKT/mTOR signaling pathway in human bladder cancer cells. Mar. Drugs, 2017, 15(8), E238.
[http://dx.doi.org/10.3390/md15080238] [PMID: 28767067]
[34]
Bonjardim, C.A. Viral exploitation of the MEK/ERK pathway - A tale of vaccinia virus and other viruses. Virology, 2017, 507, 267-275.
[http://dx.doi.org/10.1016/j.virol.2016.12.011] [PMID: 28526201]
[35]
Jiang, R.; Lopez, V.; Kelleher, S.L.; Lönnerdal, B. Apo- and holo-lactoferrin are both internalized by lactoferrin receptor via clathrin-mediated endocytosis but differentially affect ERK-signaling and cell proliferation in Caco-2 cells. J. Cell. Physiol., 2011, 226(11), 3022-3031.
[http://dx.doi.org/10.1002/jcp.22650] [PMID: 21935933]
[36]
Samatar, A.A.; Poulikakos, P.I. Targeting RAS-ERK signalling in cancer: Promises and challenges. Nat. Rev. Drug Discov., 2014, 13(12), 928-942.
[http://dx.doi.org/10.1038/nrd4281] [PMID: 25435214]
[37]
Cao, Y.; Liang, H.; Zhang, F.; Luan, Z.; Zhao, S.; Wang, X.A.; Liu, S.; Bao, R.; Shu, Y.; Ma, Q.; Zhu, J.; Liu, Y. Prohibitin overexpression predicts poor prognosis and promotes cell proliferation and invasion through ERK pathway activation in gallbladder cancer. J. Exp. Clin. Cancer Res., 2016, 35(1), 68.
[http://dx.doi.org/10.1186/s13046-016-0346-7] [PMID: 27084680]
[38]
Yang, X.S.; Liu, S.A.; Liu, J.W.; Yan, Q. Fucosyltransferase IV enhances expression of MMP-12 stimulated by EGF via the ERK1/2, p38 and NF-κB pathways in A431 cells. Asian Pac. J. Cancer Prev., 2012, 13(4), 1657-1662.
[http://dx.doi.org/10.7314/APJCP.2012.13.4.1657] [PMID: 22799384]
[39]
Si, W.; Shen, J.; Du, C.; Chen, D.; Gu, X.; Li, C.; Yao, M.; Pan, J.; Cheng, J.; Jiang, D.; Xu, L.; Bao, C.; Fu, P.; Fan, W. A miR-20a/MAPK1/c-Myc regulatory feedback loop regulates breast carcinogenesis and chemoresistance. Cell Death Differ., 2018, 25(2), 406-420.
[http://dx.doi.org/10.1038/cdd.2017.176] [PMID: 29125598]

Rights & Permissions Print Cite
Article Metrics
4
© 2024 Bentham Science Publishers | Privacy Policy