Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Mini-Review Article

The Therapeutic Potential of Urolithin A for Cancer Treatment and Prevention

Author(s): Vladimir S. Rogovskii*

Volume 22, Issue 9, 2022

Published on: 28 June, 2022

Page: [717 - 724] Pages: 8

DOI: 10.2174/1568009622666220602125343

Price: $65

conference banner
Abstract

Background: Urolithin A is the metabolite of natural polyphenol ellagic acid and ellagitannins generated by gut microbiota. Urolithin A is better absorbed in the gastrointestinal tract than its parent substances. Thus, the variable effects of ellagitannin-reach food (like pomegranate fruit, walnuts, tea, and others) on people's health might be linked with the differences in individual microbiota content. Urolithin A possesses various anti-inflammatory and anti-cancer effects, as shown by in vivo and in vitro studies.

Objectives: In the current review, we consider anti-inflammatory and direct anti-cancer urolithin A effects as well as their molecular mechanisms, which might be the basement of clinical trials, estimating urolithin A anti-cancer effects.

Conclusion: Urolithin A attenuated the pro-inflammatory factors production (IL-6, IL-1β, NOS2 and others) in vitro studies. Oral urolithin A treatment caused prominent anti-cancer and anti-inflammatory action in various in vivo studies, including colitis rat model, carrageenan-induced paw edema mice model, models of pancreatic cancer, and models of obesity. The main molecular mechanisms of these effects might be the modulation of aryl hydrocarbon receptors, which antagonism may lead to decreasing of chronic inflammation. Other primary targets of urolithin A might be the processes of protein phosphorylation (for instance, it decreases the phosphorylation of protein kinase B) and p53 stabilization. Anti-inflammatory effects of urolithin A can be reached in physiologically relevant concentrations. This might be of vital importance for preventing immune suppression associated with chronic inflammation in cancer. Considering the favorable urolithin A safety profile, it is a promising compound for cancer treatment and prevention.

Keywords: Urolithin A, polyphenols, inflammation, cancer, AhR antagonist, ellagitannins.

Graphical Abstract
[1]
Muku, G.; Murray, I.; Espín, J.; Perdew, G.; Urolithin, A. Urolithin A is a dietary microbiota-derived human aryl hydrocarbon receptor antagonist. Metabolites, 2018, 8(4), 86.
[http://dx.doi.org/10.3390/metabo8040086] [PMID: 30501068]
[2]
Yang, X.; Tomás-Barberán, F.A. Tea is a significant dietary source of ellagitannins and ellagic acid. J. Agric. Food Chem., 2019, 67(19), 5394-5404.
[http://dx.doi.org/10.1021/acs.jafc.8b05010] [PMID: 30339026]
[3]
Xia, B.; Shi, X.C.; Xie, B.C.; Zhu, M.Q.; Chen, Y.; Chu, X.Y.; Cai, G.H.; Liu, M.; Yang, S.Z.; Mitchell, G.A.; Pang, W.J.; Wu, J.W. Uro-lithin A exerts antiobesity effects through enhancing adipose tissue thermogenesis in mice. PLoS Biol., 2020, 18(3), e3000688.
[http://dx.doi.org/10.1371/journal.pbio.3000688] [PMID: 32218572]
[4]
Ghosh, N.; Das, A.; Biswas, N.; Gnyawali, S.; Singh, K.; Gorain, M.; Polcyn, C.; Khanna, S.; Roy, S.; Sen, C.K. Urolithin A augments angiogenic pathways in skeletal muscle by bolstering NAD+ and SIRT1. Sci. Rep., 2020, 10(1), 20184.
[http://dx.doi.org/10.1038/s41598-020-76564-7] [PMID: 33214614]
[5]
Al-Harbi, S.A.; Abdulrahman, A.O.; Zamzami, M.A.; Khan, M.I. Urolithins: The gut based polyphenol metabolites of ellagitannins in cancer prevention, a review. Front. Nutr., 2021, 8, 647582.
[http://dx.doi.org/10.3389/fnut.2021.647582] [PMID: 34164422]
[6]
Giménez-Bastida, J.A.; Ávila-Gálvez, M.Á.; Espín, J.C.; González-Sarrías, A. The gut microbiota metabolite urolithin A, but not other relevant urolithins, induces p53-dependent cellular senescence in human colon cancer cells. Food Chem. Toxicol., 2020, 139, 111260.
[http://dx.doi.org/10.1016/j.fct.2020.111260] [PMID: 32179165]
[7]
Okumura, T. The potential as new treatment agent of Urolithin-A metabolized from ellagic acid by gut microbiota in cancer., 2021, 67(2), 131-139.
[8]
Rønning, S.B.; Voldvik, V.; Bergum, S.K.; Aaby, K.; Borge, G.I.A. Ellagic acid and urolithin A modulate the immune response in LPS-stimulated U937 monocytic cells and THP-1 differentiated macrophages. Food Funct., 2020, 11(9), 7946-7959.
[http://dx.doi.org/10.1039/C9FO03008E] [PMID: 32832941]
[9]
Toney, A.M.; Fox, D.; Chaidez, V.; Ramer-Tait, A.E.; Chung, S. Immunomodulatory role of urolithin a on metabolic diseases. Biomedicines, 2021, 9(2), 192.
[http://dx.doi.org/10.3390/biomedicines9020192] [PMID: 33671880]
[10]
Abdelazeem, K.N.M.; Kalo, M.Z.; Beer-Hammer, S.; Lang, F. The gut microbiota metabolite urolithin A inhibits NF-κB activation in LPS stimulated BMDMs. Sci. Rep., 2021, 11(1), 7117.
[http://dx.doi.org/10.1038/s41598-021-86514-6] [PMID: 33782464]
[11]
Rogovskii, V. Immune tolerance as the physiologic counterpart of chronic inflammation. Front. Immunol., 2020, 11, 2061.
[http://dx.doi.org/10.3389/fimmu.2020.02061] [PMID: 33117330]
[12]
Rogovskii, V.S. The linkage between inflammation and immune tolerance: Interfering with inflammation in cancer. Curr. Cancer Drug Targets, 2017, 17(4), 325-332.
[http://dx.doi.org/10.2174/1568009617666170109110816] [PMID: 28067176]
[13]
Setrerrahmane, S.; Xu, H. Tumor-related interleukins: Old validated targets for new anti-cancer drug development. Mol. Cancer, 2017, 16(1), 153.
[http://dx.doi.org/10.1186/s12943-017-0721-9] [PMID: 28927416]
[14]
Rogovskii, V. Modulation of inflammation-induced tolerance in cancer. Front. Immunol., 2020, 11, 1180.
[http://dx.doi.org/10.3389/fimmu.2020.01180] [PMID: 32676076]
[15]
Totiger, T.M.; Srinivasan, S.; Jala, V.R.; Lamichhane, P.; Dosch, A.R.; Gaidarski, A.A., III; Joshi, C.; Rangappa, S.; Castellanos, J.; Vemu-la, P.K.; Chen, X.; Kwon, D.; Kashikar, N.; VanSaun, M.; Merchant, N.B.; Nagathihalli, N.S. Urolithin A, a novel natural compound to tar-get PI3K/AKT/mTOR pathway in pancreatic cancer. Mol. Cancer Ther., 2019, 18(2), 301-311.
[http://dx.doi.org/10.1158/1535-7163.MCT-18-0464] [PMID: 30404927]
[16]
Bobowska, A.; Granica, S.; Filipek, A.; Melzig, M.F.; Moeslinger, T.; Zentek, J.; Kruk, A.; Piwowarski, J.P. Comparative studies of uro-lithins and their phase II metabolites on macrophage and neutrophil functions. Eur. J. Nutr., 2021, 60(4), 1957-1972.
[http://dx.doi.org/10.1007/s00394-020-02386-y] [PMID: 32960290]
[17]
Wang, Y.; Qiu, Z.; Zhou, B.; Liu, C.; Ruan, J.; Yan, Q.; Liao, J.; Zhu, F. In vitro antiproliferative and antioxidant effects of urolithin A, the colonic metabolite of ellagic acid, on hepatocellular carcinomas HepG2 cells. Toxicol. In Vitro, 2015, 29(5), 1107-1115.
[http://dx.doi.org/10.1016/j.tiv.2015.04.008] [PMID: 25910917]
[18]
Giridharan, S.; Srinivasan, M. Mechanisms of NF-κB p65 and strategies for therapeutic manipulation. J. Inflamm. Res., 2018, 11, 407-419.
[http://dx.doi.org/10.2147/JIR.S140188] [PMID: 30464573]
[19]
Komatsu, W.; Kishi, H.; Yagasaki, K.; Ohhira, S. Urolithin A attenuates pro-inflammatory mediator production by suppressing PI3-K/Akt/NF-κB and JNK/AP-1 signaling pathways in lipopolysaccharide-stimulated RAW264 macrophages: Possible involvement of NADPH oxidase-derived reactive oxygen species. Eur. J. Pharmacol., 2018, 833, 411-424.
[http://dx.doi.org/10.1016/j.ejphar.2018.06.023] [PMID: 29932926]
[20]
Rogovskii, V.S.; Popov, S.V.; Sturov, N.V.; Shimanovskii, N.L. The possibility of preventive and therapeutic use of green tea catechins in prostate cancer. Anticancer. Agents Med. Chem., 2019, 19(10), 1223-1231.
[http://dx.doi.org/10.2174/1871520619666190404153058] [PMID: 30947675]
[21]
Zhang, H.Y.; Chen, L.L.; Li, X.J.; Zhang, J. Evolutionary inspirations for drug discovery. Trends Pharmacol. Sci., 2010, 31(10), 443-448.
[http://dx.doi.org/10.1016/j.tips.2010.07.003] [PMID: 20724009]
[22]
Leláková, V.; Šmejkal, K.; Jakubczyk, K.; Veselý, O.; Landa, P.; Václavík, J. Bobáľ P.; Pížová, H.; Temml, V.; Steinacher, T.; Schuster, D.; Granica, S.; Hanáková, Z.; Hošek, J. Parallel in vitro and in silico investigations into anti-inflammatory effects of non-prenylated stil-benoids. Food Chem., 2019, 285, 431-440.
[http://dx.doi.org/10.1016/j.foodchem.2019.01.128] [PMID: 30797367]
[23]
Avgerinos, K.I.; Spyrou, N.; Mantzoros, C.S.; Dalamaga, M. Obesity and cancer risk: Emerging biological mechanisms and perspectives. Metabolism, 2019, 92, 121-135.
[http://dx.doi.org/10.1016/j.metabol.2018.11.001] [PMID: 30445141]
[24]
Deng, T.; Lyon, C.J.; Bergin, S.; Caligiuri, M.A.; Hsueh, W.A. Obesity, inflammation, and cancer. Annu. Rev. Pathol., 2016, 11(1), 421-449.
[http://dx.doi.org/10.1146/annurev-pathol-012615-044359] [PMID: 27193454]
[25]
Venkateswaran, N.; Conacci-Sorrell, M. Kynurenine: An oncometabolite in colon cancer. Cell Stress, 2020, 4(1), 24-26.
[http://dx.doi.org/10.15698/cst2020.01.210] [PMID: 31922097]
[26]
Zhang, S.; Al-Maghout, T.; Cao, H.; Pelzl, L.; Salker, M.S.; Veldhoen, M.; Cheng, A.; Lang, F.; Singh, Y. Gut bacterial metabolite Urolithin A (UA) mitigates Ca2+ entry in T cells by regulating miR-10a-5p. Front. Immunol., 2019, 10, 1737.
[http://dx.doi.org/10.3389/fimmu.2019.01737] [PMID: 31417547]
[27]
Cheng, F.; Dou, J.; Zhang, Y.; Wang, X.; Wei, H.; Zhang, Z.; Cao, Y.; Wu, Z.; Urolithin, A. Urolithin a inhibits epithelial–mesenchymal transition in lung cancer cells via P53-Mdm2-Snail pathway. OncoTargets Ther., 2021, 14, 3199-3208.
[http://dx.doi.org/10.2147/OTT.S305595] [PMID: 34040386]
[28]
Ahsan, A.; Zheng, Y.R.; Wu, X.L.; Tang, W.D.; Liu, M.R.; Ma, S.J.; Jiang, L.; Hu, W.W.; Zhang, X.N.; Chen, Z. Urolithin A- activated autophagy but not mitophagy protects against ischemic neuronal injury by inhibiting ER stress in vitro and in vivo. CNS Neurosci. Ther., 2019, 25(9), 976-986.
[http://dx.doi.org/10.1111/cns.13136] [PMID: 30972969]
[29]
Zhao, W.; Shi, F.; Guo, Z.; Zhao, J.; Song, X.; Yang, H. Metabolite of ellagitannins, urolithin A induces autophagy and inhibits metastasis in human sw620 colorectal cancer cells. Mol. Carcinog., 2018, 57(2), 193-200.
[http://dx.doi.org/10.1002/mc.22746] [PMID: 28976622]
[30]
Singh, A.; D’Amico, D.; Andreux, P.A.; Dunngalvin, G.; Kern, T.; Blanco-Bose, W.; Auwerx, J.; Aebischer, P.; Rinsch, C. Direct supple-mentation with Urolithin A overcomes limitations of dietary exposure and gut microbiome variability in healthy adults to achieve con-sistent levels across the population. Eur. J. Clin. Nutr., 2022, 76(2), 297-308.
[PMID: 34117375]
[31]
Smith, B.N.; Burton, L.J.; Henderson, V.; Randle, D.D.; Morton, D.J.; Smith, B.A.; Taliaferro-Smith, L.; Nagappan, P.; Yates, C.; Zayzafoon, M.; Chung, L.W.K.; Odero-Marah, V.A. Snail promotes epithelial mesenchymal transition in breast cancer cells in part via ac-tivation of nuclear ERK2. PLoS One, 2014, 9(8), e104987.
[http://dx.doi.org/10.1371/journal.pone.0104987] [PMID: 25122124]
[32]
Norden, E.; Heiss, E.H. Urolithin A gains in antiproliferative capacity by reducing the glycolytic potential via the p53/TIGAR axis in colon cancer cells. Carcinogenesis, 2019, 40(1), 93-101.
[http://dx.doi.org/10.1093/carcin/bgy158] [PMID: 30418550]
[33]
Sánchez-González, C.; Ciudad, C.J.; Izquierdo-Pulido, M.; Noé, V. Urolithin A causes p21 up-regulation in prostate cancer cells. Eur. J. Nutr., 2016, 55(3), 1099-1112.
[http://dx.doi.org/10.1007/s00394-015-0924-z] [PMID: 25962506]
[34]
Alauddin, M.; Okumura, T.; Rajaxavier, J.; Khozooei, S.; Pöschel, S.; Takeda, S.; Singh, Y.; Brucker, S.Y.; Wallwiener, D.; Koch, A.; Salk-er, M.S. Gut bacterial metabolite urolithin a decreases actin polymerization and migration in cancer cells. Mol. Nutr. Food Res., 2020, 64(7), 1900390.
[http://dx.doi.org/10.1002/mnfr.201900390] [PMID: 31976617]
[35]
El-Wetidy, M.S.; Ahmad, R.; Rady, I.; Helal, H.; Rady, M.I.; Vaali-Mohammed, M.A.; Al-Khayal, K.; Traiki, T.B.; Abdulla, M.H. Urolithin A induces cell cycle arrest and apoptosis by inhibiting Bcl-2, increasing p53-p21 proteins and reactive oxygen species production in colo-rectal cancer cells. Cell Stress Chaperones, 2021, 26(3), 473-493.
[http://dx.doi.org/10.1007/s12192-020-01189-8] [PMID: 33666815]
[36]
Alzahrani, A.M.; Shait Mohammed, M.R.; Alghamdi, R.A.; Ahmad, A.; Zamzami, M.A.; Choudhry, H.; Khan, M.I. Urolithin A and B alter cellular metabolism and induce metabolites associated with apoptosis in leukemic cells. Int. J. Mol. Sci., 2021, 22(11), 5465.
[http://dx.doi.org/10.3390/ijms22115465] [PMID: 34067305]
[37]
Xue, P.; Fu, J.; Zhou, Y. The Aryl hydrocarbon receptor and tumor immunity. Front. Immunol., 2018, 9, 286.
[http://dx.doi.org/10.3389/fimmu.2018.00286] [PMID: 29487603]
[38]
Zhan, T.; Rindtorff, N.; Boutros, M. Wnt signaling in cancer. Oncogene, 2017, 36(11), 1461-1473.
[http://dx.doi.org/10.1038/onc.2016.304] [PMID: 27617575]
[39]
Zhang, W.; Chen, J.H.; Aguilera-Barrantes, I.; Shiau, C.W.; Sheng, X.; Wang, L.S.; Stoner, G.D.; Huang, Y.W. Urolithin A suppresses the proliferation of endometrial cancer cells by mediating estrogen receptor-α-dependent gene expression. Mol. Nutr. Food Res., 2016, 60(11), 2387-2395.
[http://dx.doi.org/10.1002/mnfr.201600048] [PMID: 27342949]
[40]
Fedotcheva, T.A.; Fedotcheva, N.I.; Shimanovsky, N.L. Progestins as anticancer drugs and chemosensitizers, new targets and applications. Pharmaceutics, 2021, 13(10), 1616.
[http://dx.doi.org/10.3390/pharmaceutics13101616] [PMID: 34683909]
[41]
Heilman, J.; Andreux, P.; Tran, N.; Rinsch, .C Safety assessment of Urolithin A, a metabolite produced by the human gut microbiota upon dietary intake of plant derived ellagitannins and ellagic acid Food Chem. Toxicol, 2017, 108(Pt A), pp. 289-297.
[42]
Andreux, P.A.; Blanco-Bose, W.; Ryu, D.; Burdet, F.; Ibberson, M.; Aebischer, P.; Auwerx, J.; Singh, A.; Rinsch, C. The mitophagy activa-tor urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nat. Metab., 2019, 1(6), 595-603.
[http://dx.doi.org/10.1038/s42255-019-0073-4] [PMID: 32694802]
[43]
Espín, J.C.; Larrosa, M.; García-Conesa, M.T.; Tomás-Barberán, F. Biological significance of urolithins, the gut microbial ellagic Acid-derived metabolites: The evidence so far. Evid. Based Complement. Alternat. Med., 2013, 2013, 1-15.
[http://dx.doi.org/10.1155/2013/270418] [PMID: 23781257]
[44]
Giménez-Bastida, J.A.; González-Sarrías, A.; Larrosa, M.; Tomás-Barberán, F.; Espín, J.C.; García-Conesa, M.T. Ellagitannin metabolites, urolithin A glucuronide and its aglycone urolithin A, ameliorate TNF-α-induced inflammation and associated molecular markers in human aortic endothelial cells. Mol. Nutr. Food Res., 2012, 56(5), 784-796.
[http://dx.doi.org/10.1002/mnfr.201100677] [PMID: 22648625]
[45]
González-Sarrías, A.; Giménez-Bastida, J.A.; Núñez-Sánchez, M.Á.; Larrosa, M.; García-Conesa, M.T.; Tomás-Barberán, F.A.; Espín, J.C. Phase-II metabolism limits the antiproliferative activity of urolithins in human colon cancer cells. Eur. J. Nutr., 2014, 53(3), 853-864.
[http://dx.doi.org/10.1007/s00394-013-0589-4] [PMID: 24077694]
[46]
Ávila-Gálvez, M.Á.; Espín, J.C.; González-Sarrías, A. Physiological relevance of the antiproliferative and estrogenic effects of dietary polyphenol aglycones versus their phase-II metabolites on breast cancer cells: A call of caution. J. Agric. Food Chem., 2018, 66(32), 8547-8555.
[http://dx.doi.org/10.1021/acs.jafc.8b03100] [PMID: 30025453]
[47]
Ávila-Gálvez, M.A.; Giménez-Bastida, J.A.; González-Sarrías, A.; Espín, J.C. Tissue deconjugation of urolithin A glucuronide to free uro-lithin A in systemic inflammation. Food Funct., 2019, 10(6), 3135-3141.
[http://dx.doi.org/10.1039/C9FO00298G] [PMID: 31041969]
[48]
Larrosa, M.; González-Sarrías, A.; Yáñez-Gascón, M.J.; Selma, M.V.; Azorín-Ortuño, M.; Toti, S.; Tomás-Barberán, F.; Dolara, P.; Espín, J.C. Anti-inflammatory properties of a pomegranate extract and its metabolite urolithin-A in a colitis rat model and the effect of colon in-flammation on phenolic metabolism. J. Nutr. Biochem., 2010, 21(8), 717-725.
[http://dx.doi.org/10.1016/j.jnutbio.2009.04.012] [PMID: 19616930]
[49]
Singh, R.; Chandrashekharappa, S.; Bodduluri, S.R.; Baby, B.V.; Hegde, B.; Kotla, N.G.; Hiwale, A.A.; Saiyed, T.; Patel, P.; Vijay-Kumar, M.; Langille, M.G.I.; Douglas, G.M.; Cheng, X.; Rouchka, E.C.; Waigel, S.J.; Dryden, G.W.; Alatassi, H.; Zhang, H.G.; Haribabu, B.; Vemula, P.K.; Jala, V.R. Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Nat. Commun., 2019, 10(1), 89.
[http://dx.doi.org/10.1038/s41467-018-07859-7] [PMID: 30626868]
[50]
Ishimoto, H.; Shibata, M.; Myojin, Y.; Ito, H.; Sugimoto, Y.; Tai, A.; Hatano, T. In vivo anti-inflammatory and antioxidant properties of ellagitannin metabolite urolithin A. Bioorg. Med. Chem. Lett., 2011, 21(19), 5901-5904.
[http://dx.doi.org/10.1016/j.bmcl.2011.07.086] [PMID: 21843938]
[51]
Nair, A.; Jacob, S. A simple practice guide for dose conversion between animals and human. J. Basic Clin. Pharm., 2016, 7(2), 27-31.
[http://dx.doi.org/10.4103/0976-0105.177703] [PMID: 27057123]
[52]
Nagathihalli, N.S.; Castellanos, J.A.; Shi, C.; Beesetty, Y.; Reyzer, M.L.; Caprioli, R.; Chen, X.; Walsh, A.J.; Skala, M.C.; Moses, H.L.; Merchant, N.B. Signal transducer and activator of transcription 3, Mediated remodeling of the tumor microenvironment results in en-hanced tumor drug delivery in a mouse model of pancreatic cancer. Gastroenterology, 2015, 149(7), 1932-1943.e9.
[http://dx.doi.org/10.1053/j.gastro.2015.07.058] [PMID: 26255562]

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