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Current Cancer Drug Targets, 2022, 22, 717-724 

MINI-REVIEW ARTICLE
ISSN: 1568-0096
eISSN: 1873-5576

The Therapeutic Potential of Urolithin A for Cancer Treatment and Impact

Factor:
2.912

Prevention The international

journal for

timely indepth

Reviews & Research

on Drug

Targets for

Cancer

BENTHAM
SCIENCE

Vladimir S. Rogovskii1,*

1
Department of Molecular Pharmacology and Radiobiology, Pirogov Russian National Research Medical University,
Moscow, Russia

Abstract: Background: Urolithin A is the metabolite of natural polyphenol ellagic acid and ellagitan-
nins generated by gut microbiota. Urolithin A is better absorbed in the gastrointestinal tract than its par-
ent 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 ef-
ARTICLE HISTORY fects as well as their molecular mechanisms, which might be the basement of clinical trials, estimating
urolithin A anti-cancer effects.
Received: February 18, 2022
Revised: April 05, 2022 Conclusion: Urolithin A attenuated the pro-inflammatory factors production (IL-6, IL-1β, NOS2 and
Accepted: April 11, 2022
others) in vitro studies. Oral urolithin A treatment caused prominent anti-cancer and anti-inflammatory
DOI: action in various in vivo studies, including colitis rat model, carrageenan-induced paw edema mice
10.2174/1568009622666220602125343
model, models of pancreatic cancer, and models of obesity. The main molecular mechanisms of these
Current Cancer Drug Targets

effects might be the modulation of aryl hydrocarbon receptors, which antagonism may lead to decreas-
ing 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 stabiliza-
tion. 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 inflam-
mation 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.

1. INTRODUCTION Depending on the resulting type of produced urolithins,

individuals metabolizing ellagic acid and ellagitannins into
Urolithin A is the metabolite of natural polyphenol ellag-
urolithins are categorized into three groups (metabotypes).
ic acid and ellagitannins generated by gut microbiota [1].
The level of this substance is dependent on two major factors Producers of urolithin A are classified as metabotype A,
– the consumption of its precursors and the individual com- while the producers of urolithin A, iso-urolithin A, and uro-
position of the microbiota. Ellagitannins are considered to be lithin B are classified as metabotype B. Those that do not
the main precursors of urolithins. Ellagitannins are polyphe- produce any of the urolithins are classified under metabotype
nols found in many plant foods, especially in pomegranate 0 [5].
fruit, strawberry, walnuts, and tea [2]. Interindividual differences in gut microbiota composition
Ellagitannins are metabolized in the intestinal tract to el- might be the reason for different effects of some foods con-
lagic acid. Depending on microbiota composition, ellagic sidered to be health-promoting, for instance, the great disper-
acid might be converted to different urolithins – urolithin A, sion in anti-cancer effects of pomegranates consumption [6].
urolithin B, urolithin C, urolithin D, and iso-urolithin A. Urolithin A possesses various immune-modulatory and
Among urolithins, the urolithin A level probably is mainly direct anti-cancer properties, widely studied in modern re-
associated with health benefits from the consumption of el- search [7-10]. These two components of urolithin A action
lagitannin-reach food [3, 4]. are responsible for its final anti-cancer effects, which might
be achieved in concentrations much lower than concentra-
*Address correspondence to this author at the Department of Molecular tions required for direct urolithin A cytotoxic effects. This
Pharmacology and Radiobiology, Pirogov Russian National Research Medi-
cal University, Bolshaya Pirogovskaya st. 9a, Moscow, 119435, Russia;
review considers anti-inflammatory and direct anti-cancer
Tel.: +7 915 256 30 08; E-mail: [email protected] urolithin A effects and their molecular mechanisms, which

1-6/22 $65.00+.00 © 2022 Bentham Science Publishers

718 Current Cancer Drug Targets, 2022, Vol. 22, No. 9 Vladimir S. Rogovskii

might be the base of clinical trials estimating urolithin A components that form the NF-κB) nuclear translocation to
anti-cancer effects. the nucleus in THP-1 macrophages was observed for uro-
lithin A metabolites (urolithin A 3-O-glucuronide and 8-O-
2. UROLITHIN A - MECHANISM OF ANTI-CANCER glucuronide) than for urolithin A. The results on inhibition of
ACTION NFκB p65 nuclear translocation by urolithin A metabolites
might be more relevant to the human organism, as urolithin
2.1. Immune-mediated Mechanisms A metabolites blood level is much more prominent than the
It is widely accepted that cancer is linked to chronic in- level of parent urolithin A, and might be close to the concen-
flammation. The induction and the maintenance of low- tration used in this study (40 mcM) [16]. The study of Wang
grade, permanent inflammation might be the universal and coauthors also revealed that urolithin A suppressed the
mechanism of immune tolerance [11]. Inflammatory factors expression of NF-κB p65 in a hepatic carcinomas cell line
increase anti-inflammatory and immunosuppressive factors, (HepG2) [17].
resulting in a positive-negative feedback loop (at first, in- Increased NF-κB p65-mediated transactivation is in-
flammation reinforces itself, eventually, it reduces itself by volved in the pathogenesis of multiple chronic inflammatory
suppressing the immune response). Thus, proinflammatory diseases, which are often associated with cancer. Currently,
factors start to play an unexpected immunosuppressive role many substances are evaluated for selective targeting of p65
in the case of chronic inflammation [12]. in the context of chronic inflammation [18].
In the first stages of carcinogenesis, inflammation can be In the work of Komatsu and coauthors, LPS-induced
caused by chronic processes (such as persistent infection, translocation of p65 in murine macrophages (RAW264 cell
nutritional imbalances, like high omega-6/omega-3 ratio, line) was also evaluated. This study has revealed that uro-
long-term contact with irritants, etc.). This first step of lithin A attenuated the pro-inflammatory factors production
chronic inflammation results in local immunosuppression. in LPS-stimulated RAW264 and mouse peritoneal macro-
Thereby, mutant cells can readily proliferate instead of being phages, suppressing the NF-κB and activator protein-1 (AP-
eliminated. Advanced tumors can promote the inflammatory 1) activation. Urolithin A also was shown to inhibit the
microenvironment by themselves, producing various in- phosphorylation of protein kinase B (AKT) and c-Jun N-
flammatory factors [13], and this permits the induction of terminal kinase (JNK). Pretreatment with 10 and 40 mcM
immune tolerance at the tumor site [12]. It is difficult to at- urolithin A inhibited the LPS-induced translocation of p65.
tenuate tumor-promoting inflammation affecting only one According to this study, urolithin A also restored the level of
factor. Substances that can influence versatile targets in the IκBα (inhibitor of nuclear factor kappa B) protein, which
pathologic mechanisms of chronic inflammation hold more normally prevents NF-κB nuclear translocation. Thus, the
promise, and urolithin A is one of such promising com- prevention of IκB degradation might be an important part of
pounds [14]. urolithin A anti-inflammatory mechanism of action [19]. IκB
Multiple studies confirm urolithin A as a potent sub- degradation is usually caused by the ubiquitin-proteasome
stance to reduce inflammation [9]. Urolithin A treatment (20 system, which is activated by IκB kinase (IKK)-mediated
mg/kg/day, by oral gavage) can result in reprogramming of phosphorylation.
the tumor immune microenvironment, as evidenced by re- Numerous other studies have shown that urolithin A can
duced levels of infiltrating immunosuppressive cell popula- modulate the processes of protein phosphorylation [15, 16,
tions such as myeloid-derived suppressor cells (MDSCs), 19]. At the molecular level, polyphenols (to which urolithin
tumor-associated macrophages (TAMs), and regulatory T- A belongs) provide increased electron density. They can
cells (Tregs) without decreasing the overall CD3 T-cells in serve as hydrogen bond donors to many proteins and nucleic
murine pancreatic tumors [15]. acid targets [20-22]. This can serve as a molecular basis for
A recent study has evaluated the effect of urolithins as modulation of protein phosphorylation processes by urolithin
well as their phase II conjugates, mainly glucuronides, on A.
functions of THP-1-derived macrophages (THP-1 - human Urolithin A reduced the pro-inflammatory cytokine pro-
monocytes cell line), murine RAW 264.7 macrophages, pri- duction and mRNA expression in LPS-stimulated murine
mary human peripheral blood mononuclear cell (PBMCs)- bone marrow-derived macrophages. The minimal concentra-
derived macrophages, and neutrophils. Urolithin A (40 mi- tion used in the described study was 25 µM. Treatment with
cromol/L (mcM) was shown to suppress TNF-α production urolithin A was able to induce significant depressions in IL-
by lipopolysaccharide (LPS)-induced THP-1-derived macro- 1β, IL-6, IL-12, TNF-α, and NOS2 expression with values
phages and human PBMCs-derived macrophages. The in- near to unstimulated control. Interestingly, administration of
duction of ERK1/2 phosphorylation by urolithin A might be urolithin A to LPS-stimulated bone marrow-derived macro-
the mechanism of this action. Interestingly, phase II metabo- phages induced remarkable decreases in TLR4 expression. In
lism was shown to result in the loss of these urolithin A ef- addition, urolithin A blunted mitogen-activated protein ki-
fects [16]. nase activation and suppressed AKT and protein kinase
In addition, the authors of this study have shown that mTOR (mammalian target of rapamycin) stimulation in-
studied compounds, including urolithin glucuronides influ- duced by LPS-stimulation in murine macrophages [10].
enced the nuclear factor-κB (NF-κB transcription factor - The study of urolithin A as a novel anti-obesity agent al-
nuclear factor kappa-light-chain-enhancer of activated B so has shown the lower concentrations of TNF-α and IL-6 in
cells) pathway. Of particular interest is the fact that much urolithin A-treated mice than in controls [3]. In addition,
stronger inhibition of NFκB p65 (p65, or RelA, is one of the
The Therapeutic Potential of Urolithin A for Cancer Treatment Current Cancer Drug Targets, 2022, Vol. 22, No. 9 719

there is evidence that obesity and obesity-induced inflamma- cally relevant concentrations. It was demonstrated that uro-
tion are associated with an increased risk of cancer [23, 24]. lithin A (1,5 mcM) triggers autophagy in SW620 colorectal
cancer cells. The apoptosis of SW620 cells by urolithin A is
There are several mechanisms by which urolithin A can
achieved in much more significant concentrations (30 mcM)
affect immune function. Urolithin A is an aryl hydrocarbon
receptor ligand, and aryl hydrocarbon receptors (AhR) are [29].
widely expressed by immune cells. Anti-inflammatory char- According to the recent study by Giménez-Bastida and
acteristics of urolithin A can be at least partly linked to AhR. coauthors, urolithin A but not other urolithins (Uro-C, IsoU-
Urolithin A was shown to act as an AhR antagonist [1]. Per- ro-A, or Uro-B), induced p53-dependent cellular senescence
sistent AhR activation by tumor-produced factors (for in- in human colon cancer cells (HCT-116 cells). The long ex-
stance, L-kynurenine) favors the expression of protective posure (2 weeks) of various human colon cancer cell lines to
TGFβ and Tregs differentiation, leading to immune evasion urolithin A (10 μΜ and sometimes 1 μM) reduced their
and survival of cancer cells [1, 25]. Thus, AhR antagonism clonogenic growth. Interestingly, urolithin A glucuronide
might be an important component of urolithin A anti-cancer and urolithin A sulphate did not exert significant inhibition
properties. on cell proliferation and cellular senescence [6]. One of the
important conclusions from these results is that urolithin A
It was also shown that urolithin A is involved in the up-
regulation of miRNA miR-10a-5p with subsequent down- might exert anti-cancer properties in concentrations of 1 μM,
which might be seen in human plasma for unchanged uro-
regulation of store-operated Ca2+ influx in murine CD4+ T
lithin A [30].
cells leading to suppression of their activation. Urolithin A
increases the expression of miR-10-5p in a dose-dependent Recently, it was shown that urolithin A dose-dependently
manner, which in turn reduces calcium release-activated cal- upregulated epithelial markers and downregulated mesen-
cium (CRAC) channel protein Orai1, and endoplasmic retic- chymal markers in lung cancer cells. Urolithin A (10 μM)
ulum calcium sensors STIM1/2 (transcript and protein lev- inhibits epithelial-mesenchymal transition (EMT) in lung
els) thus blunting store-operated Ca2+ entry (SOCE) in mu- cancer cells (A549 and H460 cells) by controlling mainly
rine CD4+ T cells [26]. Snail expression. The molecular mechanism of EMT inhibi-
tion by urolithin A disrupts the interaction of p53 and mdm2
The above-mentioned results indicate that urolithin A
genes (mdm2 - murine double minute 2, serves as a mediator
could be used as a natural immune-modulator during various
chronic inflammatory disorders which are associated with that promotes Snail degradation via ubiquitination), which
leads to Snail ubiquitination and degradation. It was suggest-
cancer. Besides immune-mediated action, urolithin A is ca-
ed that urolithin A stabilizes p53 to increase mdm2 levels,
pable of direct anti-cancer action. However, the molecular
ubiquitinating Snail protein (Fig. 1). Snail is the transcrip-
mechanisms of immune-modulatory as well as anti-cancer
tional factor involved in the repression of epithelial marker
action, might be similar (Fig. 1).
E-cadherin expression [27]. A snail transcription factor is
up-regulated in several cancers and associated with increased
2.2. Direct Anti-cancer Action tumor migration via induction of EMT [31].
Urolithin A can downregulate several oncogenes such as Urolithin A also was shown to have an antiproliferative
mTOR and Kirsten-rat sarcoma viral oncogene homolog capacity reducing the glycolytic potential via the
(KRAS) and upregulate tumor suppressor genes such as p53 p53/TIGAR (TP53-induced glycolytic regulatory phospha-
[27]. tase) axis in colon cancer cells (IC50 ~ 19.6 µM after 72 h).
For instance, urolithin A targets numerous kinases down- Urolithin A exerted p53 stabilization and p53 target gene
stream of KRAS, a mutation present in the majority of pan- expression [32]. However, as follows from numerous stud-
creatic ductal adenocarcinoma (PDAC) cases, in particular, ies, the concentration of urolithin A which is required for
the PI3K/AKT/mTOR signaling pathways. At the molecular induction of apoptosis, is relatively high [5, 29, 33] and is
level, urolithin A dose-dependently decreased phosphoryla- hardly feasible in the organism. For instance, a statistically
tion of AKT at the T308 site and downstream effector of significant increase (14 %) in the apoptotic cell population of
AKT - p70S6K (70-kDa ribosomal protein S6 kinase im- LNCaP prostate cells was observed only after incubation
portant for cell growth regulation) in PDAC cell lines [15]. with 40 μM of urolithin A. It caused an evident decrease in
LNCaP cell viability at a concentration of 60 μM [33].
At the cellular and organism level, urolithin A reduced
cancer cell proliferation and increased cellular apoptosis in Urolithin A also influences the migratory capacity of
both xenograft and genetically modified mouse models sus- cancer cells, affecting the G-protein Rac1, a major regulator
ceptible to pancreatic cancer. In addition, urolithin A (5 of the actin cell cytoskeleton, essential for cell motility. Rac1
mcM) reduced the migration capacity of PDAC cells. At the was found to be overexpressed in many cancers, and loss of
same time, it is important to note that urolithin A has mini- Rac1 activity suppresses tumor growth. Urolithin A (20
mal impact on normal pancreatic epithelial cells, such as mcM) disrupts the expression and function of the G-protein
human pancreatic epithelial nestin-expressing cells (HPNE) Rac1 and p21 protein-activated kinase 1 (PAK1), decreasing
and HPNE-KRAS [15]. actin polymerization and migration in Ishikawa cells, a well-
differentiated type 1 endometrial carcinoma cell line [34].
Urolithin A was also shown to increase an autophagy ef-
fect in certain cell types [28]. According to the new study of El-Wetidy and coauthors,
Urolithin A also induces cell cycle arrest and apoptosis by
The data on autophagy induction by urolithin A is of par-
inhibiting the anti-apoptotic protein Bcl-2 expression and
ticular importance because they are obtained in physiologi-
720 Current Cancer Drug Targets, 2022, Vol. 22, No. 9 Vladimir S. Rogovskii

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Fig. (1). The main mechanisms of immune-modulatory and anti-cancer action of urolithin A are depicted. The possible primary targets of
urolithin A are circled. Among them are Aryl hydrocarbon Receptors (AhR), which antagonism may lead to decreasing chronic inflamma-
tion. Other primary targets are the processes of protein phosphorylation and p53 stabilization, which might be modulated by urolithin A.

increasing the expression of the pro-apoptotic proteins p53 dometrial cell lines by mediating estrogen receptor-α-
and p21 in colorectal cancer cell lines (at concentrations of dependent gene expression [39]. It is well-known that the
25 mcM and more) [35]. imbalance between the expression of estrogen and progester-
Urolithin A-induced apoptosis and inhibited the prolif- one receptors is of vital importance for the tumor transfor-
mation of hormone-sensitive tumors [40].
eration of leukemic cell lines Jurkat and K562 with IC50
close to 25 mcM. It was observed that urolithin treatment Thus, urolithin A possesses various anti-cancer effects,
alters glutamine metabolism and increases the level of and the concentration required to affect cancer cell physiolo-
LysoPC, prostaglandin F1a, and palmitoleic in leukemic gy starts from approximately 1 μM in case of long-term in-
cells. These fatty acids are a marker for apoptosis [36]. cubation [6]. Such concentration is feasible in human blood
plasma [30]. However, as follows from above, for reaching
Urolithin A was identified as a selective AhR antagonist
antiproliferative capacity, much higher urolithin A levels are
with a relatively high affinity. Urolithin A repressed AhR-
required
driven (mediated by AhR ligand indoxyl 3-sulfate) reporter
expression in human HepG2 (40/6) cells with an IC50 ~ 3
µM. AhR is necessary for urolithin A-mediated attenuation 3. UROLITHIN A - SAFETY AND PHARMACOKI-
of IL-6 and prostaglandin-endoperoxide synthase 2 (PTGS2) NETIC PROFILE
expression in human colorectal adenocarcinoma cells (Caco- Generally, urolithin A was shown to have a favorable
2 cells). Interestingly, urolithin A (10 mcM) was capable of safety profile in vivo and in clinical trials.
attenuating both basal and cytokine-induced IL6 mRNA lev-
els by Caco-2 cells [1]. Basal cytokine production by cancer The 28-day and 90-day studies in Wistar rats (up to 5.0%
cells might be involved in the promotion of chronic inflam- urolithin A mixed in diet) showed no alterations in clinical
mation in the tumor microenvironment. parameters and did not indicate any specific toxic mecha-
nisms. The genotoxicity assays demonstrated that urolithin A
AhR is activated constitutively in various tumors and fa- is not genotoxic [7, 41].
cilitates their expansion by regulating growth-promoting
genes [25, 37]. AhR antagonism can suppress tumor growth No serious adverse events and no product-related non-
of different tumor types, for instance, it attenuates aggressive serious adverse events were reported during the phase 1 clin-
phenotypes in head and neck tumor cell lines [1]. ical trial in which urolithin A was administered over 4
weeks, to healthy, sedentary elderly individuals [42].
Another target that is affected by urolithin A is Wnt sig-
naling. Aberrant activation of the Wnt signaling pathways is Urolithins are better absorbed in the gastrointestinal tract
observed in most colorectal cancers and many other cancer than their parent substances (ellagitannins) [2]. After absorp-
entities [38]. tion, urolithins reach the liver and undergo phase 2 biotrans-
formation, to yield various conjugated forms [9]. Urolithins
Estrogen receptors are also, to a certain extent, targeted circulate in plasma mainly as conjugates (e.g., glucuronide
by urolithin A. It suppressed the proliferation of various en-
The Therapeutic Potential of Urolithin A for Cancer Treatment Current Cancer Drug Targets, 2022, Vol. 22, No. 9 721

and sulfate) at concentrations in the range of 0.2–20 μM [42, shortening of colons, gut permeability, and inflammation)
43]. As in the case with other polyphenols, an important [49].
question arises if the urolithin metabolites are as active as the
Besides effects against chronic inflammation, urolithin A
parent substances. According to the various studies, urolithin
was shown to exert effects in models of acute inflammation.
A metabolites possess different pharmacological effects. For It showed an anti-inflammatory effect on carrageenan-
instance, urolithin A glucuronide (5-15 μM) was shown to
induced paw edema in mice. Administration of urolithin A
inhibit monocyte adhesion and endothelial cell migration of
(300 mg/kg, orally) 1 hour before carrageenan injection re-
human aortic endothelial cells in a significant manner [44].
duced the volume of paw edema. Total plasma urolithin A
In another study, urolithin A glucuronides showed lower
levels in this study reached 3.9 mcM 1 hour after ingestion
antiproliferative activity than their aglycone counterparts in
and decreased to 1.3 mcM at 6 hours. Interestingly, treatment
the HT-29 human colon cancer cell line [45]. Another work with urolithin A at 6 hours before inflammatory induction by
showed that polyphenol aglycones, including urolithin A,
carrageenan showed no effect. In addition, plasma in treated
exerted dose-dependent antiproliferative and estrogen-
mice exhibited increased oxygen radical antioxidant capacity
ic/antiestrogenic activities, but both their glucuronide and
(ORAC) - increased to 142% at 1 hour after administration,
sulfate conjugates lacked these activities [46].
with a reduction to 118% of the control scores at 6 hours
A recent study by Giménez-Bastida and coauthors re- after administration [50]. These results showed that blood
vealed that phase-II metabolism of urolithins limited the in- levels of urolithin A (or its metabolites) after oral admin-
duction of senescence in human colorectal cancer cell lines istration are sufficient to exert anti-inflammatory effects.
[6]. However, according to a recent study in a rat model of
If we converse these animal doses to human doses, divid-
systemic inflammation induced by LPS, urolithin A glucu-
ing rat's dose by 6,2 and mice's dose by 12,3 (based on nor-
ronide might be the subject of tissue deconjugation to free
malization of dose to relative body surface area [51]), we
urolithin A in systemic inflammation [47]. will obtain a human dose of 2,4 mg/kg and 24 mg/kg respec-
Eventually, it might be concluded that, to some extent, tively for the study of Larrosa et al. and Ishimoto et al. As
urolithin A metabolites retain the pharmacological activity of we can see, relatively high doses of urolithin A are potent in
the parent substance. Additionally, deconjugation processes management of acute inflammation. In contrast, relatively
might be the mechanism of free urolithin A appearance near low doses in case of long-term treatment might exert uro-
the biological targets. However, in some cases, urolithin A lithin A activity against chronic inflammation, which is
glucuronides exert a more prominent effect than the parent linked to cancer.
substance, for instance, the effect of inhibition of NFκB p65
In the above-mentioned work of Totiger and coauthors,
nuclear translocation [16].
urolithin A was studied in xenograft mice. Mouse xenografts
were generated using a subcutaneous flank injection of tu-
4. THE RESULTS OF IN VIVO EXPERIMENTS mor cells (pancreatic ductal adenocarcinoma cell lines) into
Although urolithin A is a promising substance for cancer athymic nude mice. Urolithin A treatment (20 mg/kg/day,
treatment, it is relatively new, and there are no clinical stud- oral gavage) initiated when the subcutaneous tumors had
ies of urolithin A activity in cancer yet. That’s why data been already established, reduced tumor growth in xenograft
mostly come from in vitro and in vivo models, including mice with signs of stopping tumor growth in comparison
those, where urolithin activity is studied against cancer- with vehicle-treated xenograft mice. In the work of Totiger
predisposing conditions, such as chronic inflammation and and coauthors, Urolithin A also was studied in PKT
obesity. Anti-inflammatory and anti-cancer properties of mice [15]. Genetically engineered mice (Ptf1acre/+; LSL-
urolithin A were demonstrated in different in vivo models. KrasG12D/+; Tgfbr2flox/flox - PKT mice) used in described study
For instance, urolithin A preserved colonic architecture and represent the closest stromal approximation to human pan-
showed anti-inflammatory properties (decrease in mRNA creatic ductal adenocarcinoma development [52]. These mice
and protein levels of cyclooxygenase 2) in the dextran sodi- spontaneously develop pancreatic cancer by 4.5 weeks of
um sulfate (DSS)-induced colitis rat model. In this study, age. The median overall survival (OS) of PKT mice is
male Fisher rats were fed with 15 mg/kg of urolithin A per around 59 days. Urolithin A (20 mg/kg/day, oral gavage)
day for 25 days, and DSS (5%) was administered for the five and/or gemcitabine (20 mg/kg, twice-weekly intraperitoneal
last days [48]. injections) were initiated at 4 weeks of age. Only urolithin A
and a combination of urolithin A and gemcitabine improved
In another study, urolithin A effect was examined in the survival with statistical significance (OS = 71 days). Howev-
2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced mice er, the urolithin A and gemcitabine combination did not pro-
colitis model. Oral treatment with urolithin A (20 mg/kg at vide any additional survival advantage over urolithin A
12 hours intervals) protected from TNBS-induced body monotherapy [15].
weight loss, reduced disease activity index and intestinal
permeability, neutrophil infiltration, and level of serum in- Urolithin A also can mitigate factors predisposing to can-
flammatory markers (IL-6, TNF-α, CXCL1, and IL-1β). In- cer. According to the above-mentioned study of Xia and co-
terestingly, in this study, urolithin A revealed therapeutic authors, urolithin A showed antiobesity effects against both
effects in case of prophylactic administration (pre-treated high-fat diet-induced and genetic obesity. Mice kept on a
mice were significantly protected from TNBS-induced colon high-fat diet were treated with 30 mg/kg/day of urolithin A
shortening and colonic inflammation) as well as in therapeu- or orlistat (FDA-approved drug for obesity management) or
tic regimen (mice treated with urolithin A 24 hours post- vehicle for 6 weeks. Urolithin A-treated mice and orlistat-
TNBS showed the reversed colitis phenotype with reducing treated mice showed significantly lower body weight (about
722 Current Cancer Drug Targets, 2022, Vol. 22, No. 9 Vladimir S. Rogovskii

25% lower) сompared to vehicle controls. Food consumption IκBα = Inhibitor of Nuclear Factor Kappa B
was approximately the same between the groups [3]. Thus,
IKK = Inhibitor of Nuclear Factor Kappa B Kinase
in vivo studies show that urolithin A has the capacity to treat
cancer and chronic inflammation, as well as predisposing mRNA = Messenger Ribonucleic Acid
conditions. IL-1β = Interleukin 1 Beta
CONCLUSION IL-6 = Interleukin 6

As seen above, urolithin A possesses various anti-cancer IL-12 = Interleukin 12

mechanisms, mainly studied in vitro. These mechanisms are NOS2 = Nitric Oxide Synthase 2
largely associated with the versatile effects of urolithin A at
TLR4 = Toll-like Receptor 4
the level of intracellular signaling pathways. They contribute
to both the anti-inflammatory effects of urolithin A and its mTOR = Mammalian Target of Rapamycin
direct antitumor effects. These effects are unlikely to mediate AhR = Aryl Hydrocarbon Receptors
a quick cure for the disease. However, they can influence the
underlying pathophysiology of cancer, which can lead to an TGFβ = Transforming Growth Factor Beta
improved prognosis. miRNA = microRNA
Taking into account the possible transition of urolithin A CRAC = Calcium Release-activated Calcium
to clinical use, major attention should be paid to mechanisms
SOCE = Store-operated Ca2+ Entry
that exist in the physiologically relevant concentrations of
unchanged urolithin A (which are sometimes less than 1 KRAS = Kirsten Rat Sarcoma Virus
mcM) or its metabolites, mainly glucuronides, whose levels PDAC = Pancreatic Ductal Adenocarcinoma
can be as high as 20 mcM in blood plasma. Most studies of
urolithin A are performed using unchanged urolithin A; that PI3K = PhosphoInositide 3-kinases
is why results obtained in concentrations of around 1 mcM p70S6K = 70-kDa Ribosomal Protein S6 Kinase
are of particular importance as they can reflect anti-cancer
HPNE = Human Pancreatic Nestin Expressing Cells
mechanisms in the human organism. More high concentra-
tions also matter, especially in the areas like the intestine and Uro-C = Urolithin C
bladder, where concentrations of urolithin A might be much Uro-B = Urolithin B
higher. However, it should be mentioned that clinical studies
of urolithin anti-cancer effects are still absent. Such studies, IsoUro-A = Iso-Urolithin A
especially long-term studies of treatment and prevention of EMT = Epithelial-mesenchymal Transition
different cancer types, could open up prospects for urolithin
A transition to clinical practice. mdm2 = Murine Double Minute 2
TIGAR = TP53-induced Glycolytic Regulatory Phospha-
AUTHORS’ CONTRIBUTIONS
tase
The author confirms being the sole contributor of this
PAK1 = p21 Protein-activated Kinase 1
work and has approved it for publication.
LysoPC = LysophosPhatidylCholines
LIST OF ABBREVIATIONS DSS = Dextran Sodium Sulfate
MDSCs = Myeloid-derived Suppressor Cells TNBS = 2,4,6-triNitroBenzene Sulfonic Acid
TAMs = Tumor-associated Macrophages CXCL1 = C-X-C Motif Chemokine Ligand 1
Tregs = Regulatory T-cells FDA = Food and Drug Administration
PBMCs = Human Peripheral Blood Mononuclear Cells
CONSENT FOR PUBLICATION
mcM = Micromoles Per Liter
Not applicable.
TNF-α = Tumor Necrosis Factor alpha
LPS = Lipopolysaccharide FUNDING
ERK1/2 = Extracellular Regulated Kinase 1/2 None.
NF-κB = Transcription Factor - Nuclear Factor kappa-
light-chain-enhancer of Activated B Cells CONFLICT OF INTEREST
RelA = v-Rel Reticuloendotheliosis Viral Oncogene The author declares no conflict of interest, financial or
Homolog A (p65) otherwise.
AP-1 = Activator Protein-1
ACKNOWLEDGEMENTS
AKT = Protein Kinase B
Declared none.
JNK = c-Jun N-Terminal Kinase
The Therapeutic Potential of Urolithin A for Cancer Treatment Current Cancer Drug Targets, 2022, Vol. 22, No. 9 723

REFERENCES [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
[1] Muku, G.; Murray, I.; Espín, J.; Perdew, G.; Urolithin, A. Urolithin A, the colonic metabolite of ellagic acid, on hepatocellular carci-
A is a dietary microbiota-derived human aryl hydrocarbon receptor nomas HepG2 cells. Toxicol. in vitro, 2015, 29(5), 1107-1115.
antagonist. Metabolites, 2018, 8(4), 86. http://dx.doi.org/10.1016/j.tiv.2015.04.008 PMID: 25910917
http://dx.doi.org/10.3390/metabo8040086 PMID: 30501068 [18] Giridharan, S.; Srinivasan, M. Mechanisms of NF-κB p65 and
[2] Yang, X.; Tomás-Barberán, F.A. Tea is a significant dietary source strategies for therapeutic manipulation. J. Inflamm. Res., 2018, 11,
of ellagitannins and ellagic acid. J. Agric. Food Chem., 2019, 407-419.
67(19), 5394-5404. http://dx.doi.org/10.2147/JIR.S140188 PMID: 30464573
http://dx.doi.org/10.1021/acs.jafc.8b05010 PMID: 30339026 [19] Komatsu, W.; Kishi, H.; Yagasaki, K.; Ohhira, S. Urolithin A at-
[3] Xia, B.; Shi, X.C.; Xie, B.C.; Zhu, M.Q.; Chen, Y.; Chu, X.Y.; Cai, tenuates pro-inflammatory mediator production by suppressing
G.H.; Liu, M.; Yang, S.Z.; Mitchell, G.A.; Pang, W.J.; Wu, J.W. PI3-K/Akt/NF-κB and JNK/AP-1 signaling pathways in lipopoly-
Urolithin A exerts antiobesity effects through enhancing adipose saccharide-stimulated RAW264 macrophages: Possible involve-
tissue thermogenesis in mice. PLoS Biol., 2020, 18(3), e3000688. ment of NADPH oxidase-derived reactive oxygen species. Eur. J.
http://dx.doi.org/10.1371/journal.pbio.3000688 PMID: 32218572 Pharmacol., 2018, 833, 411-424.
[4] Ghosh, N.; Das, A.; Biswas, N.; Gnyawali, S.; Singh, K.; Gorain, http://dx.doi.org/10.1016/j.ejphar.2018.06.023 PMID: 29932926
M.; Polcyn, C.; Khanna, S.; Roy, S.; Sen, C.K. Urolithin A aug- [20] Rogovskii, V.S.; Popov, S.V.; Sturov, N.V.; Shimanovskii, N.L.
ments angiogenic pathways in skeletal muscle by bolstering NAD+ The possibility of preventive and therapeutic use of green tea cate-
and SIRT1. Sci. Rep., 2020, 10(1), 20184. chins in prostate cancer. Anticancer. Agents Med. Chem., 2019,
http://dx.doi.org/10.1038/s41598-020-76564-7 PMID: 33214614 19(10), 1223-1231.
[5] Al-Harbi, S.A.; Abdulrahman, A.O.; Zamzami, M.A.; Khan, M.I. http://dx.doi.org/10.2174/1871520619666190404153058 PMID:
Urolithins: The gut based polyphenol metabolites of ellagitannins 30947675
in cancer prevention, a review. Front. Nutr., 2021, 8, 647582. [21] Zhang, H.Y.; Chen, L.L.; Li, X.J.; Zhang, J. Evolutionary inspira-
http://dx.doi.org/10.3389/fnut.2021.647582 PMID: 34164422 tions for drug discovery. Trends Pharmacol. Sci., 2010, 31(10),
[6] Giménez-Bastida, J.A.; Ávila-Gálvez, M.Á.; Espín, J.C.; González- 443-448.
Sarrías, A. The gut microbiota metabolite urolithin A, but not other http://dx.doi.org/10.1016/j.tips.2010.07.003 PMID: 20724009
relevant urolithins, induces p53-dependent cellular senescence in [22] Leláková, V.; Šmejkal, K.; Jakubczyk, K.; Veselý, O.; Landa, P.;
human colon cancer cells. Food Chem. Toxicol., 2020, 139, Václavík, J.; Bobáľ, P.; Pížová, H.; Temml, V.; Steinacher, T.;
111260. Schuster, D.; Granica, S.; Hanáková, Z.; Hošek, J. Parallel in vitro
http://dx.doi.org/10.1016/j.fct.2020.111260 PMID: 32179165 and in silico investigations into anti-inflammatory effects of non-
[7] Okumura, T. The potential as new treatment agent of Urolithin-A prenylated stilbenoids. Food Chem., 2019, 285, 431-440.
metabolized from ellagic acid by gut microbiota in cancer. 2021, http://dx.doi.org/10.1016/j.foodchem.2019.01.128 PMID:
67(2), 131-139. 30797367
[8] Rønning, S.B.; Voldvik, V.; Bergum, S.K.; Aaby, K.; Borge, G.I.A. [23] Avgerinos, K.I.; Spyrou, N.; Mantzoros, C.S.; Dalamaga, M. Obe-
Ellagic acid and urolithin A modulate the immune response in LPS- sity and cancer risk: Emerging biological mechanisms and perspec-
stimulated U937 monocytic cells and THP-1 differentiated macro- tives. Metabolism, 2019, 92, 121-135.
phages. Food Funct., 2020, 11(9), 7946-7959. http://dx.doi.org/10.1016/j.metabol.2018.11.001 PMID: 30445141
http://dx.doi.org/10.1039/C9FO03008E PMID: 32832941 [24] Deng, T.; Lyon, C.J.; Bergin, S.; Caligiuri, M.A.; Hsueh, W.A.
[9] Toney, A.M.; Fox, D.; Chaidez, V.; Ramer-Tait, A.E.; Chung, S. Obesity, inflammation, and cancer. Annu. Rev. Pathol., 2016,
Immunomodulatory role of urolithin a on metabolic diseases. Bio- 11(1), 421-449.
medicines, 2021, 9(2), 192. http://dx.doi.org/10.1146/annurev-pathol-012615-044359 PMID:
http://dx.doi.org/10.3390/biomedicines9020192 PMID: 33671880 27193454
[10] Abdelazeem, K.N.M.; Kalo, M.Z.; Beer-Hammer, S.; Lang, F. The [25] Venkateswaran, N.; Conacci-Sorrell, M. Kynurenine: An on-
gut microbiota metabolite urolithin A inhibits NF-κB activation in cometabolite in colon cancer. Cell Stress, 2020, 4(1), 24-26.
LPS stimulated BMDMs. Sci. Rep., 2021, 11(1), 7117. http://dx.doi.org/10.15698/cst2020.01.210 PMID: 31922097
http://dx.doi.org/10.1038/s41598-021-86514-6 PMID: 33782464 [26] Zhang, S.; Al-Maghout, T.; Cao, H.; Pelzl, L.; Salker, M.S.; Veld-
[11] Rogovskii, V. Immune tolerance as the physiologic counterpart of hoen, M.; Cheng, A.; Lang, F.; Singh, Y. Gut bacterial metabolite
chronic inflammation. Front. Immunol., 2020, 11, 2061. Urolithin A (UA) mitigates Ca2+ entry in T cells by regulating miR-
http://dx.doi.org/10.3389/fimmu.2020.02061 PMID: 33117330 10a-5p. Front. Immunol., 2019, 10, 1737.
[12] Rogovskii, V.S. The linkage between inflammation and immune http://dx.doi.org/10.3389/fimmu.2019.01737 PMID: 31417547
tolerance: Interfering with inflammation in cancer. Curr. Cancer [27] Cheng, F.; Dou, J.; Zhang, Y.; Wang, X.; Wei, H.; Zhang, Z.; Cao,
Drug Targets, 2017, 17(4), 325-332. Y.; Wu, Z.; Urolithin, A. Urolithin a inhibits epithelial–
http://dx.doi.org/10.2174/1568009617666170109110816 PMID: mesenchymal transition in lung cancer cells via P53-Mdm2-Snail
28067176 pathway. OncoTargets Ther., 2021, 14, 3199-3208.
[13] Setrerrahmane, S.; Xu, H. Tumor-related interleukins: Old validat- http://dx.doi.org/10.2147/OTT.S305595 PMID: 34040386
ed targets for new anti-cancer drug development. Mol. Cancer, [28] Ahsan, A.; Zheng, Y.R.; Wu, X.L.; Tang, W.D.; Liu, M.R.; Ma,
2017, 16(1), 153. S.J.; Jiang, L.; Hu, W.W.; Zhang, X.N.; Chen, Z. Urolithin A‐
http://dx.doi.org/10.1186/s12943-017-0721-9 PMID: 28927416 activated autophagy but not mitophagy protects against ischemic
[14] Rogovskii, V. Modulation of inflammation-induced tolerance in neuronal injury by inhibiting ER stress in vitro and in vivo. CNS
cancer. Front. Immunol., 2020, 11, 1180. Neurosci. Ther., 2019, 25(9), 976-986.
http://dx.doi.org/10.3389/fimmu.2020.01180 PMID: 32676076 http://dx.doi.org/10.1111/cns.13136 PMID: 30972969
[15] Totiger, T.M.; Srinivasan, S.; Jala, V.R.; Lamichhane, P.; Dosch, [29] Zhao, W.; Shi, F.; Guo, Z.; Zhao, J.; Song, X.; Yang, H. Metabolite
A.R.; Gaidarski, A.A., III; Joshi, C.; Rangappa, S.; Castellanos, J.; of ellagitannins, urolithin A induces autophagy and inhibits metas-
Vemula, P.K.; Chen, X.; Kwon, D.; Kashikar, N.; VanSaun, M.; tasis in human sw620 colorectal cancer cells. Mol. Carcinog., 2018,
Merchant, N.B.; Nagathihalli, N.S. Urolithin A, a novel natural 57(2), 193-200.
compound to target PI3K/AKT/mTOR pathway in pancreatic can- http://dx.doi.org/10.1002/mc.22746 PMID: 28976622
cer. Mol. Cancer Ther., 2019, 18(2), 301-311. [30] Singh, A.; D’Amico, D.; Andreux, P.A.; Dunngalvin, G.; Kern, T.;
http://dx.doi.org/10.1158/1535-7163.MCT-18-0464 PMID: Blanco-Bose, W.; Auwerx, J.; Aebischer, P.; Rinsch, C. Direct
30404927 supplementation with Urolithin A overcomes limitations of dietary
[16] Bobowska, A.; Granica, S.; Filipek, A.; Melzig, M.F.; Moeslinger, exposure and gut microbiome variability in healthy adults to
T.; Zentek, J.; Kruk, A.; Piwowarski, J.P. Comparative studies of achieve consistent levels across the population. Eur. J. Clin. Nutr.,
urolithins and their phase II metabolites on macrophage and neu- 2022, 76(2), 297-308.
trophil functions. Eur. J. Nutr., 2021, 60(4), 1957-1972. PMID: 34117375
http://dx.doi.org/10.1007/s00394-020-02386-y PMID: 32960290 [31] Smith, B.N.; Burton, L.J.; Henderson, V.; Randle, D.D.; Morton,
724 Current Cancer Drug Targets, 2022, Vol. 22, No. 9 Vladimir S. Rogovskii

D.J.; Smith, B.A.; Taliaferro-Smith, L.; Nagappan, P.; Yates, C.; Biological significance of urolithins, the gut microbial ellagic Ac-
Zayzafoon, M.; Chung, L.W.K.; Odero-Marah, V.A. Snail pro- id-derived metabolites: The evidence so far. Evid. Based Comple-
motes epithelial mesenchymal transition in breast cancer cells in ment. Alternat. Med., 2013, 2013, 1-15.
part via activation of nuclear ERK2. PLoS One, 2014, 9(8), http://dx.doi.org/10.1155/2013/270418 PMID: 23781257
e104987. [44] Giménez-Bastida, J.A.; González-Sarrías, A.; Larrosa, M.; Tomás-
http://dx.doi.org/10.1371/journal.pone.0104987 PMID: 25122124 Barberán, F.; Espín, J.C.; García-Conesa, M.T. Ellagitannin metab-
[32] Norden, E.; Heiss, E.H. Urolithin A gains in antiproliferative ca- olites, urolithin A glucuronide and its aglycone urolithin A, amelio-
pacity by reducing the glycolytic potential via the p53/TIGAR axis rate TNF-α-induced inflammation and associated molecular mark-
in colon cancer cells. Carcinogenesis, 2019, 40(1), 93-101. ers in human aortic endothelial cells. Mol. Nutr. Food Res., 2012,
http://dx.doi.org/10.1093/carcin/bgy158 PMID: 30418550 56(5), 784-796.
[33] Sánchez-González, C.; Ciudad, C.J.; Izquierdo-Pulido, M.; Noé, V. http://dx.doi.org/10.1002/mnfr.201100677 PMID: 22648625
Urolithin A causes p21 up-regulation in prostate cancer cells. Eur. [45] González-Sarrías, A.; Giménez-Bastida, J.A.; Núñez-Sánchez,
J. Nutr., 2016, 55(3), 1099-1112. M.Á.; Larrosa, M.; García-Conesa, M.T.; Tomás-Barberán, F.A.;
http://dx.doi.org/10.1007/s00394-015-0924-z PMID: 25962506 Espín, J.C. Phase-II metabolism limits the antiproliferative activity
[34] Alauddin, M.; Okumura, T.; Rajaxavier, J.; Khozooei, S.; Pöschel, of urolithins in human colon cancer cells. Eur. J. Nutr., 2014,
S.; Takeda, S.; Singh, Y.; Brucker, S.Y.; Wallwiener, D.; Koch, A.; 53(3), 853-864.
Salker, M.S. Gut bacterial metabolite urolithin a decreases actin http://dx.doi.org/10.1007/s00394-013-0589-4 PMID: 24077694
polymerization and migration in cancer cells. Mol. Nutr. Food Res., [46] Ávila-Gálvez, M.Á.; Espín, J.C.; González-Sarrías, A. Physiologi-
2020, 64(7), 1900390. cal relevance of the antiproliferative and estrogenic effects of die-
http://dx.doi.org/10.1002/mnfr.201900390 PMID: 31976617 tary polyphenol aglycones versus their phase-II metabolites on
[35] El-Wetidy, M.S.; Ahmad, R.; Rady, I.; Helal, H.; Rady, M.I.; breast cancer cells: A call of caution. J. Agric. Food Chem., 2018,
Vaali-Mohammed, M.A.; Al-Khayal, K.; Traiki, T.B.; Abdulla, 66(32), 8547-8555.
M.H. Urolithin A induces cell cycle arrest and apoptosis by inhibit- http://dx.doi.org/10.1021/acs.jafc.8b03100 PMID: 30025453
ing Bcl-2, increasing p53-p21 proteins and reactive oxygen species [47] Ávila-Gálvez, M.A.; Giménez-Bastida, J.A.; González-Sarrías, A.;
production in colorectal cancer cells. Cell Stress Chaperones, 2021, Espín, J.C. Tissue deconjugation of urolithin A glucuronide to free
26(3), 473-493. urolithin A in systemic inflammation. Food Funct., 2019, 10(6),
http://dx.doi.org/10.1007/s12192-020-01189-8 PMID: 33666815 3135-3141.
[36] Alzahrani, A.M.; Shait Mohammed, M.R.; Alghamdi, R.A.; Ah- http://dx.doi.org/10.1039/C9FO00298G PMID: 31041969
mad, A.; Zamzami, M.A.; Choudhry, H.; Khan, M.I. Urolithin A [48] Larrosa, M.; González-Sarrías, A.; Yáñez-Gascón, M.J.; Selma,
and B alter cellular metabolism and induce metabolites associated M.V.; Azorín-Ortuño, M.; Toti, S.; Tomás-Barberán, F.; Dolara, P.;
with apoptosis in leukemic cells. Int. J. Mol. Sci., 2021, 22(11), Espín, J.C. Anti-inflammatory properties of a pomegranate extract
5465. and its metabolite urolithin-A in a colitis rat model and the effect of
http://dx.doi.org/10.3390/ijms22115465 PMID: 34067305 colon inflammation on phenolic metabolism. J. Nutr. Biochem.,
[37] Xue, P.; Fu, J.; Zhou, Y. The Aryl hydrocarbon receptor and tumor 2010, 21(8), 717-725.
immunity. Front. Immunol., 2018, 9, 286. http://dx.doi.org/10.1016/j.jnutbio.2009.04.012 PMID: 19616930
http://dx.doi.org/10.3389/fimmu.2018.00286 PMID: 29487603 [49] Singh, R.; Chandrashekharappa, S.; Bodduluri, S.R.; Baby, B.V.;
[38] Zhan, T.; Rindtorff, N.; Boutros, M. Wnt signaling in cancer. On- Hegde, B.; Kotla, N.G.; Hiwale, A.A.; Saiyed, T.; Patel, P.; Vijay-
cogene, 2017, 36(11), 1461-1473. Kumar, M.; Langille, M.G.I.; Douglas, G.M.; Cheng, X.; Rouchka,
http://dx.doi.org/10.1038/onc.2016.304 PMID: 27617575 E.C.; Waigel, S.J.; Dryden, G.W.; Alatassi, H.; Zhang, H.G.;
[39] Zhang, W.; Chen, J.H.; Aguilera-Barrantes, I.; Shiau, C.W.; Sheng, Haribabu, B.; Vemula, P.K.; Jala, V.R. Enhancement of the gut
X.; Wang, L.S.; Stoner, G.D.; Huang, Y.W. Urolithin A suppresses barrier integrity by a microbial metabolite through the Nrf2 path-
the proliferation of endometrial cancer cells by mediating estrogen way. Nat. Commun., 2019, 10(1), 89.
receptor-α-dependent gene expression. Mol. Nutr. Food Res., 2016, http://dx.doi.org/10.1038/s41467-018-07859-7 PMID: 30626868
60(11), 2387-2395. [50] Ishimoto, H.; Shibata, M.; Myojin, Y.; Ito, H.; Sugimoto, Y.; Tai,
http://dx.doi.org/10.1002/mnfr.201600048 PMID: 27342949 A.; Hatano, T. In vivo anti-inflammatory and antioxidant properties
[40] Fedotcheva, T.A.; Fedotcheva, N.I.; Shimanovsky, N.L. Progestins of ellagitannin metabolite urolithin A. Bioorg. Med. Chem. Lett.,
as anticancer drugs and chemosensitizers, new targets and applica- 2011, 21(19), 5901-5904.
tions. Pharmaceutics, 2021, 13(10), 1616. http://dx.doi.org/10.1016/j.bmcl.2011.07.086 PMID: 21843938
http://dx.doi.org/10.3390/pharmaceutics13101616 PMID: [51] Nair, A.; Jacob, S. A simple practice guide for dose conversion
34683909 between animals and human. J. Basic Clin. Pharm., 2016, 7(2), 27-
[41] Heilman, J.; Andreux, P.; Tran, N.; Rinsch, C. Safety assessment of 31.
Urolithin A, a metabolite produced by the human gut microbiota http://dx.doi.org/10.4103/0976-0105.177703 PMID: 27057123
upon dietary intake of plant derived ellagitannins and ellagic ac- [52] Nagathihalli, N.S.; Castellanos, J.A.; Shi, C.; Beesetty, Y.; Reyzer,
id.Food Chem. Toxicol, 2017, 108(Pt A), pp. 289-297. M.L.; Caprioli, R.; Chen, X.; Walsh, A.J.; Skala, M.C.; Moses,
[42] Andreux, P.A.; Blanco-Bose, W.; Ryu, D.; Burdet, F.; Ibberson, H.L.; Merchant, N.B. Signal transducer and activator of transcrip-
M.; Aebischer, P.; Auwerx, J.; Singh, A.; Rinsch, C. The mitopha- tion 3, Mediated remodeling of the tumor microenvironment results
gy activator urolithin A is safe and induces a molecular signature of in enhanced tumor drug delivery in a mouse model of pancreatic
improved mitochondrial and cellular health in humans. Nat. cancer. Gastroenterology, 2015, 149(7), 1932-1943.e9.
Metab., 2019, 1(6), 595-603. http://dx.doi.org/10.1053/j.gastro.2015.07.058 PMID: 26255562
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.