Special Reviews Juntendo Medical Journal 2021. 67(2),131-139 The Potential as New Treatment Agent of Urolithin-A Metabolized from Ellagic Acid by Gut Microbiota in Cancer TOSHIYUKI OKUMURA＊1) 2) ＊1)Department of Womenʼs Health,Eberhard Karls University of Tuebingen,Land Baden-Württemberg,Germany, ＊2)Department of Obstetrics and Gynecology,Juntendo University Faculty of Medicine,Tokyo,Japan Cancer is the leading cause of death in Japan. Cancer is treated by multidisciplinary therapy such as surgery, chemotherapy,molecular target therapy and radiotherapy. However,almost of advanced cancer relapse after treatment. The relapsed cancer acquires resistance to the therapeutic agents we already used. The prognosis of relapsed cancer is very poor. Therefore,new treatment agents are needed urgently. In recent years metabolites derived from natural foods are focused as new therapeutic agents of cancer diseases. The metabolites are expected to cause less side effect than chemotherapy and have same effect as chemotherapy to cancer. Furthermore therapeutic agents from natural foods are Ellagic acid is metabolite derived from nuts,berries,and pomegranates. Ellagic acid is known to have anticancer effects,due to affecting apoptosis,cell proliferation and cell cycle regulation. Some of metabolites from ellagic acid also have anticancer effect. Urolithins are gut derived bacterial metabolites from ellagic acid. Many articles reported that Urolithin-A has anticancer effect for many cancers. Urolithin-A was reported to regulate p53 protein, caspase 3, caspase 7, AKT, aromatase and PARP in some cancers. Actin polymerization is regulated via Rac1 pathway by Urolithin-A in endometrial cancer. Furthermore, proliferation of many cancer cell lines is suppressed by UA. Safety of UA was investigated by using Rat model. The article suggested Urolithin-A has less genotoxicity compared with cyclophosphamide. Thus,Urolithin-A might be able to have a role as new treatment agent to cancer. Key words: cancer,gut microbiota,ellagic acid,Urolithin-A,new cancer therapeutic agent Cancer growth after adjuvant chemo therapy. However almost of all advanced cancer will be relapsed after The cause of cancer has not yet been clarified. treatment. The prognosis of advanced or relapse However population of cancer patient is increasing cancer is poor still now. The new treatment agent is year by year. It is common that staging of cancer is needed to be identified urgently. divided according to spread of cancer. Treatment plan for cancer is choose depends on progress of Ellagic acid cancer. Almost of all cancers are treated by surgery,chemotherapy,radiotherapy,molecular Recently component purified from natural food is target therapy,or combination of these therapeutic expected to be used as new treatment agent to approaches. These molecular target therapies are cancers. Ellagic acid is known as a metabolite derived used as treatment agent or maintenance agent. from seeds (walnuts,almonds),fruits (persimmons, Maintenance agent is used to suppress tumor berries,peaches,palms,and pomegranate) and Toshiyuki Okumura Department of Obstetrics and Gynecology,Juntendo University Faculty of Medicine 2-1-1 Hongo,Bunkyo-ku,Tokyo 113-8421,Japan TEL: +81-3-3813-3111 E-mail: [email protected] Triannual Meeting of the Juntendo Medical Society“MedicalResearch Update”〔The meeting was originally scheduled to be held on May 16, 2020,but was canceled due to COVID-19 pandemic〕 〔Received July 30, 2020〕〔Accepted Jan. 22,2021〕 Copyright © 2021 The Juntendo Medical Society. This is an open access article distributed under the terms of Creative Commons Attribution Li- cense (CC BY),which permits unrestricted use,distribution,and reproduction in any medium,provided the original source is properly credited. doi: 10.14789/jmj.2021.67.JMJ20-R17 131 Okumura T: The potential as new treatment agent of Urolithin-A metabolized from ellagic acid by gut microbiota in cancer Ellagitannins Seeds（walnuts, almonds）, Fruits（berries, palms, pomegranate, etc.） GM Vegetables Punicalagin Corilagin Vescalagin Urolithin－D Unknown Urolithin－M5 GM DE GM Urolithin－M6 Unknown DE Ellagic acid Urolithin－C Urolithin－E Urolithin－M7 Unknown DE GM：Gut microbiota Urolithin－A DE：Dehydroxylase enzyme CYP：Cytochrome P450 DE CYP enzyme Urolithin－B Figure-1 Metabolite way of seeds,fruits and vegetables to Urolithin-A Some gut microbiotas involved in metabolite way are clarified,but not all. The gut microbiota which produces Urolithin-A from Urolithin-M7 is not found. vegetables. 1) Ellagic acid derived from Ellagitan- on antioxidant function of Ellagic acid to investigate nins (Punicalagin,Corilagin and Vescalagin) 2)(Fig- neuroprotective function of Ellagic acid. The ure-1). Ellagic acid is known to have antioxidant symptom of dementia and brain damage induced by function,anti-inflammatory activity,neuroprotec- streptozotocin was decreased by Ellagic acid in tive function and anticancer effect. Ascorbic acid rats. 12) Motor impairment is improved by Ellagic and α-tocopherol are well known as antioxidant. acid due to reducing neuroinflammatory bio- Indeed,articles shows that Ellagic acid is able to markers (IL-1β and TNF-α) in lesioned rats. On eliminate activation of peroxyl radicals,nitrogen the other hand,the brain is protected against free dioxide,hydroxyl radical and peroxynitrite. 3) 4) radical induced neural damage by Ellagic acid. 13) Intriguingly,Ellagic acid is shown to reduce the Studies have shown that Ellagic acid might be able amount of 8-oxo-2ʼ-deoxyguanosine which is one of to have role as anticancer agent by regulating marker of oxidative DNA damage after DNA carcinogenesis,apoptosis,induced DNA damage damage induced by oxidative stress. 5) 6) Pathophy- due to oxidative stress and angiogenesis in various siological event of inflammation is related to cancers. Ellagic acid increased IL-6 and downregu- oxidative stress. 7) Ellagic acid deactivates AP-1 lated the expression level of pERK1/2,pSTAT3 and and MAPK that are induced by TNF-α and IL-1β. pAkt in PC3 cells which is androgen-independent However,NF- κB is activated by Ellagic acid. 8) 9) prostate cancer cell line. 14) Ellagic acid induced Furthermore,Ellagic acid regulates COX-2 mRNA apoptosis by caspase-3 activation in the transgenic expression by inhibition of ROS production that rat for prostate adenocarcinoma model. Ellagic acid inhibits NF-κB activity. 10) The regulator of COX-2 induced apoptosis by increasing Bax/Bcl-2 ratio expression is NF-κB. 11) The effect of Ellagic acid as and cell cycle related proteins cdk-2,cyclin E,p21 a neuroprotective agent has been investigated by and p27,but not cdk-1 and cyclin D1 in androgen using various assays. Almost of all articles focused dependent prostate cancer cell line,LNCaP. 15) Cell 132 Juntendo Medical Journal 67(2),2021 proliferation of HCT-15 colon adenocarcinoma cells the lactone rings to produce luteic acid. Three was decreased by Ellagic acid. Ellagic acid tetrahydroxy-urolithins,Urolithin-D,Urolithin-M6 decreased cell viability and induced cell cycle arrest and Urolithin-E are produced from Urolithin-M5. in G2/M. Cyclin D1 is decreased by Ellagic acid in Trihydroxy-urolithins,Urolithin-C and Urolithin- HCT-15 cells. Furthermore,Ellagic acid inhibited M7 are then transformed from tetrahydroxy-uroli- the PI3K/Akt pathway in HCT-15 cells. The thins. Trihydroxy-urolithins finally lead to the main expression level of caspase-3, cytochrome C and Bax metabolites,the dihydroxy-urolithin which is were increased by Ellagic acid. 16) Ellagic acid had known as Urolithin-A and the mono-hydroxy antiproliferative effect by inducing cell cycle arrest urolithin that is known as Urolithin-B 23)(Figure-1). in G0/G1 in MCF7 cells,a human breast cancer cell The literature about the bacterial species responsi- line through regulation of TGF-β/Smads signaling ble for urolithin production from ETs,or other pathway. 17) Ellagic acid showed decrease of chemo- EA-derived compounds are deficient. Recently, resistance to cisplatin in A2780CisR,a human Gordonibacter urolithinfaciens (DSM 27213T) and ovarian cancer cell line acquired resistance to G. pamelaeae (DSM 19378T) producing urolithin cisplatin by intermittent treatment with cisplatin were found in human feces. These bacteria for 26 weeks. 18) Ellagic acid inhibited growth of belonged to the family Coriobacteriaceae. 24) 25) human endometrial cancer cell line by decreasing These microbes generated Urolithin-M5,Urolithin- sodium-hydrogen antiporter 1 expression level, M6,and Urolithin-C. However,Urolithin-A and activity of Na+/H+ exchanger,glucose uptake, Urolithin-B were not produced in pure cultures. 24) lactate release and cytosolic pH. 19) HeLa cells, Other bacteria which are needed to produce human cervical cancer cell line was decreased cell Urolithin-A and Urolithin-B from precursor are proliferation by Ellagic acid by downregulation of still unknown. Studies had shown that absorption of Akt/mTOR signaling pathway via increase of Ellagic acid was poor. (Figure-1) However,Uroli- IGFB7. 20) Ellagic acid had a role as anticancer effect thin-A and -B were reported to be distributed in glioblastoma. Ellagic acid decreased cell prolifera- throughout colon,urine,feces,plasma and prostate tion and viability in U118 and U87,human glioblas- tissues following intake of foods or juices enriched toma cell line. Ellagic acid induced cell cycle arrest Ellagic acid. 26) 27) Urolithin-A and -B decreased in S phase in those cell lines. Furthermore,Ellagic endometrial cancer cell proliferation compared with acid showed same effect in glioblastoma xenograft other compounds derived from ellagitannin,antho- model. Ellagic acid inhibited tumor growth by cyanin,sugar,lignan and fiber. 28) Therefore,respon- decreasing MMP-2, MMP-9, Snail, Bcl-2, cdk-2, sibility for the health effect of Ellagic acid have been cdk6 and cyclinD1 and increasing E-cadherin suggested to be Urolithin-A and -B. expression level. Ellagic acid inhibited Notch and Akt signaling pathway. 21) Ellagic acid increased The effect of Urolithin-A apoptosis mediated ROS in B-lymphocytes taken from patients had chronic lymphocytic leukemia by 1.