Tannic Acid: Specific Form of Tannins in Cancer Chemoprevention
and Therapy-Old and New Applications
Published online: 27 March 2020
Purpose of Review This short review is aimed at providing an updated and comprehensive report on tannic acid biological
activities and molecular mechanisms of action most important for cancer prevention and adjuvant therapy.
Recent Findings Tannic acid (TA), a mixture of digallic acid esters of glucose, is a common ingredient of many foods. The early
studies of its anti-mutagenic and anti-tumorigenic activity were mostly demonstrated in the mouse skin model. This activity has been
explained by its ability to inhibit carcinogens activation, as well as antioxidant and anti-inflammatory properties. Recently, the cell cycle
arrest, apoptosis induction, reduced rate of proliferation, and cell migration and adhesion of several cancer cell lines as a result of TA
treatment were described. The underlining mechanisms include modulation of signaling pathways such as EGFR/Jak2/STATs, or
inhibition of PKM2 glycolytic enzyme. Moreover, epithelial-to-mesenchymal transition prevention and decrease of cancer stem cells
formation by TA were also reported. Besides, TAwas found to be potent chemosensitizer overcoming multidrug resistance. Eventually,
its specific physicochemical features were found useful for generation of drug-loaded nanoparticles.
Summary TA was shown to be a very versatile molecule with possible application not only in cancer prophylaxis, as was
initially thought, but also in adjuvant cancer therapy. The latter may refer to chemosensitization and its application as a part
of drug delivery systems. More studies are required to better explore this subject. In addition, the effect of TA on normal
cells and its bioavailability have to better characterized.
Keywords Tann ic acid .Mouse skin model .Cancer cells .Chemosensitization .Nanomedicine
Carcinogenesis is the process of transformation of a normal
cell into a neoplastic one. This transition involves several
steps starting with initiation, and followed by promotion and
progression. Genetic and epigenetic changes caused by exog-
enous agents or endogenous factors are driving these stages,
leading to the accumulation of mutations and epimutations in
genes responsible for cellular homeostasis. Thus, cancer de-
velopment involves gene-environment interactions.
Moreover, oxidative stress and inflammation play important
roles in carcinogenesis. Along with the epigenetic
modifications, they cause aberrant expression of a variety of
genes, both within the transforming cell population and the
cells within the surrounding lesion .
Since carcinogenesis is a complex and long multistep
process, intervention on its most early stages is considered
as the most logical and promising approach of combating
cancer. Chemoprevention is defined as the use of synthet-
ic or natural substances to reverse, suppress, or prevent
carcinogenic progression .
All of the above mentioned processes are targets for chemo-
preventive agents, and numerous reports of various bioactive
foods and their extracted compounds, including tannins, have
been shown to affect these hallmarks of carcinogenesis. Tannic
acid (TA) is a specific tannin that formally contains 10 galloyl
(3,4,5-trihydroxyphenyl) units surrounding a glucose center.
However, commercially available and often naturally occurring
TA consists of molecules with 2–12 galloyl moieties. TA con-
tains no carboxyl groups, but is weakly acidic because of the
multiplicity of phenolic hydroxyls. The hydroxyls also cause it
to be extremely soluble in water [https://www.acs.org/content/
This article is part of the Topical Collection on Redox Modulators
*Wan da Bae r-Du b o ws k a
Department of Pharmaceutical Biochemistry, Poznan University of
Medical Sciences, Święcicki 4 Str, Poznań,Poland
Current Pharmacology Reports (2020) 6:28–37
REDOX MODULATORS (C JACOB, SECTION EDITOR)
#The Author(s) 2020
the others tannins, TA is found in a wide range of plants,
including fruits, green and black teas, nuts, and grains.
However, TA major limitation in biological systems might be
its relatively poor bioavailability. The available data indicate
that following oral administration, ~ 60% of tannic acid
remains unchanged, but some are hydrolyzed to gallic acid by
tannase in the intestine and are further metabolized to 4-O-
methylgallic acid, pyrogallol, and resorcinol .In vitro bio-
availability of tannic acid was evaluated in ligated rat small
intestine segments showing 50% uptake, but not complete
transfer through the gut wall . One of the very first studies
about TA date back to 1989, when TA was found to inhibit skin,
lung, and forestomach tumors induced by chemical carcino-
gens [5••]. This activity was related to reduced carcinogens
activation resulting from inhibition of specific forms of cyto-
chrome P450, electrophile trapping, modulation of arachidonic
acid metabolism [6,7], and ultimately inhibition of DNA-
adducts formation [8,9•,10]. Similarly, to other polyphenols,
TA possesses antioxidant activity . However, it can act also
as pro-oxidant resulting in oxidative DNA damage .
In the recent years, growing number of reports describe
new mechanisms of TA activity and possible application not
only in primary chemoprevention, but also in sensitization to
conventional drugs used in anticancer therapy. Moreover, its
specific physicochemical features showed up to be useful for
nanomedicine purposes, including modern drug delivery sys-
tems (Fig. 1). This short review summarizes the current
knowledge about TA chemopreventive activity and its possi-
ble application in cancer prophylaxis and adjuvant cancer
Early Studies: Tannic Acid Affects
the Processes Involved in Initiation
and Promotion of Carcinogenesis in Mouse
Skin Carcinogenesis Model
The mouse skin model of multistage chemical carcinogenesis
represents one of the best-established in vivo models for the
study of the sequential and stepwise development of tumors.
In addition, this model can be used to evaluate both novel skin
cancer prevention strategies and the impact of genetic back-
ground and genetic manipulation on tumor initiation, promo-
tion, and progression . Therefore, the earliest data on the
anticarcinogenic activity of TA were demonstrated in this
model (Fig. 2).
In this regard, Muhtar et al. [14••] showed exceptional ac-
tivity of TA, among naturally occurring plant phenols, in the
protection against polycyclic aromatic hydrocarbons (PAH)
7,12-dimethylbenz[a]anthracene (DMBA), benzo[a]pyrene
(B[a]P), 3-methylcholanthrene (3-MC), and direct carcinogen
N-methyl-N-nitrosourea-induced skin tumorigenesis. The ini-
tiation of carcinogenesis by indirect carcinogens like PAH
requires metabolic activation to ultimate carcinogenic form,
which covalently binds to DNA. Cytochromes P450, mainly
Inhibition of cancer promotion
Induction of cell cycle arrrest
and apoptosis of cancer cells
Inhibition of cancer cells
migration, invasion and
Modulation of phase I and II drug
Inhibition of cancer cell
Inhibition of epithelial-to-
Chemosenstization and impact
on multidrug resistance
An element of anti-cancer drug
delivery systems/carrier of anti-
Fig. 1 The overview of mechanisms exerted by tannic acid important for cancer chemoprevention and/or therapy
Curr Pharmacol Rep (2020) 6:28–37 29
CYP1A1, CYP1A2, CYP1B1, and CYP2E1, are involved in
this process. Several studies including ours have shown the
ability of TA to inhibit P450 monooxygenases or its specific
isoforms [15–17]. Inhibitions of these enzymes led to the re-
duced carcinogen-DNA adduct formation in mouse epidermis
[8,18]. Interestingly, analysis of DMBA-DNA adducts
formed in vitro in the presence of 3-MC induced microsomes
and in mouse epidermis showed almost complete inhibition of
DMBA –dAdo adducts formation [9,10]. This was an im-
portant observation since the adenine adducts induced by ul-
timate DMBA metabolites (bay-region diol-epoxides) lead to
mutation at the codon 61 of c-H-Ras and consequently initiate
tumorigenesis in the mouse skin .
Moreover, modulation of phase II enzymes involved in
ultimate carcinogens deactivation by TA was also observed
both in animal models and in cell cultures in vitro.In animal
models, this effect was to some extent tissue specific .
In tissue such as mouse epidermis, the role of modulation of
enzymes involved in carcinogens activation and deactivation in
the formation of DNA-adducts by TA depended on the type of
carcinogen. While the reduction of B[a]P-DNA seems to result
from decreased B[a]P activation, in case of DMBA-DNA ad-
ducts, the scavenging or masking of the binding sites to be oc-
cupied by DMBA reactive metabolites is more probable .
Following the initiation stage, the population of mutated
cells is promoted to clonally expand during the second stage,
referred to as “promotion.”Promoting agents, which are both
structurally and mechanistically diverse, stimulate cell signal-
ing, increase production of growth factors, and generate oxi-
dative stress and tissue inflammation . Ours and the other
research groups demonstrated that TA in the mouse epidermis
stimulated by 12-O-tetradecanoyphorbol-13-acetate (TPA)
inhibited the activation of NF-κB transcription factor and sub-
sequently expression and activity of inducible isoform of ni-
tric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2)
enzymes –the key players of inflammation process . As
was mentioned above, TA through the reduction of DMBA,
dAdo adducts may protect against Ras activation, which is
required for chemical carcinogen-induced skin carcinogenesis
in mice. Tumor promoter such as TPA expends the population
of Ras initiated cells . Thus, the compounds which affect
the initiation of carcinogenesis in the mouse epidermis by
reducing DNA adducts in critical genes like Ras family may
inhibit the activation of NF-κB. The results of our studies
demonstrated that TA may act in this way, i.e., by decreasing
carcinogen-dAdo adducts formation, TA may inhibit NF-κB
activation . Moreover, TA affected also the activation of
epidermal growth factor receptor (EGFR), activator protein-1
(AP-1) transcription factor, and signal transducers and activa-
tors of transcription (STATs) signaling pathways .
Moreover, in the same model, TA down-regulated the expres-
sion and activity of protein kinase C (PKC) which is thought
to be a major intracellular receptor for the mouse skin tumor
promoter TPA .
More recently, anti-promotional activity of TA in the
mouse skin through the reduction of oxidative stress as well
as COX-2, iNOS, PCNA (proliferating cell nuclear antigen)
protein, and proinflammatory cytokine such as IL-6 release
was confirmed . Anti-inflammatory activity of TA was
also shown in the context of house dust mite–induced atopic
Chemical, physical, biological
INITIATION PROMOTION PROGRESSION
epigenetically altered cell Selective clonal expansion Tum or c el ls
Fig. 2 Tannic acid can affect cancer initiation, promotion, and progression
30 Curr Pharmacol Rep (2020) 6:28–37
dermatitis. As the underlying mechanism of this activity, the
induction of peroxisome proliferator-activated receptor
PPARγprotein was suggested [24•].
Chemopreventive activity of very low dose dietary TA ad-
ministration in hepatoma bearing C3H male mice was also
demonstrated, but the studies on the mechanism of this activ-
ity in this model were not continued . However, signifi-
cant hepatoprotective effects against acetaminophen-induced
hepatotoxicity were recently described . The authors sug-
gested that hepatoprotective mechanisms of TA may be relat-
ed to antioxidation, anti-inflammation, and anti-apoptosis,
thus the same mechanisms which might be responsible for
TA chemopreventive activity observed in early study of hep-
atoma bearing mouse model.
Tannic Acid Induces Cell Cycle Arrest,
Apoptosis, and Limits Proliferation of Various
Promising data on the anticarcinogenic effect of TA in animal
models, particularly in two-stage mouse skin model, stimulat-
ed the studies on the effect of TA on vital cellular processes
such as apoptosis and proliferation in cancer cells of different
origin. The observed effects of TA treatment often were cell-
type dependent. The examples of TA influence on cancer cell
lines of different origin are presented below.
Breast Cancer Cells
Booth et al.  performed a series of experiments in which
ER-positive breast cancer cells, MCF7, and triple negative
) MDA-MB-231 along with non-
tumorigenic MCF10A were exposed to TA-cross-linked col-
lagen type I beads. Growing cells remodeled collagen and
released TA into surrounding medium leading to caspase-
mediated apoptosis. MCF7 cells were more sensitive to the
pro-apoptotic effect of TA than MDA-MB-231. TA also in-
duced apoptosis through the same mechanism in HER-2 pos-
itive cell line BT474 [27•,28,29].
Moreover, the same group successfully loaded adipocytes
onto collagen type I beads with TA cross-linked. As adipo-
cytes attached and grew on the TA cross-linked collagen
beads, they remodeled the collagen, releasing TA, which then
interacted with HER2 breast cancer cells, leading to its apo-
ptosis. Viability assays also revealed the higher toxicity of TA
to HER21 breast cancer cells as compared to normal human
breast epithelial cells and adipocytes.
In contrast to the results of the above mentioned studies, no
differences in the sensitivity to TA between MCF7 and MDA-
MB-231 breast cancer cells were observed in the investigation
of Nie et al. . One reason of this discrepancy might be the
difference in TA concentrations applied in both studies which
make the two approaches difficult to compare. This group also
demonstrated that TA inhibits fatty acid synthase (FAS) activ-
ity. This key enzyme of fatty acids synthesis is overexpressed
in human breast cancer cells. The authors suggested that inhi-
bition of FAS may be one of the possible ways to induce
apoptosis in these cells. Interestingly, TA showed higher
cytotoxicity toward breast cancer cells than to FAS
overexpressed 3 T3-L1 adipocytes. Thus, it is possible that in
appropriate concentration, TA may induce apoptosis in cancer
cells, but not in the surrounding adipocytes.
Moreover, TA has been reported to have high tyrosine kinase
inhibition capacity. In this regard, strong inhibition of the tyrosine
kinase activity of epidermal growth factor receptor (EGFR) and a
weak inhibition of the P60 and insulin receptor tyrosine kinase
were observed as a result of the treatment of human hepatoma
HepG2 cells with TA. The molecular modeling study suggested
that TA could be docked into the ATP-binding pockets of either
EGFR or the insulin receptor . EGFR-mediated phosphory-
lation of signal transducers and activators of transcription
(STATs) leads to their activation. STATs can be activated also
in EGFR-independent manner, involving phosphorylation by
Janus kinases (JAKs). It was found that TA modulates the
EGFR/Jak2/STAT3 pathway, inducing mitochondrial apoptosis
in breast cancer cells lines: MCF-7, T47D, SK-BR 3, and MDA-
MB-231. Moreover, both the enhancement of STAT1 ser727
phosphorylation and the inhibition of STAT1 tyr701 phosphory-
lation were discovered as the key factors leading to G1 arrest
upon TA treatment .
Prostate Cancer Cells
The effect of TA on proliferation, metastasis, and invasion was
investigated in prostate cancer PC-3 and LNCaP cell lines,
representing high and low metastatic potential, respectively.
Treatment with TA significantly inhibited migration, invasion
into matrigel, and ability to form colonies by prostate cancer
cells. Modulation of the expression of cytochromes CYP17A1,
CYP3A4, CYP2B6, and phase II enzymes NQO1, GSTM1, and
GSTP1 was also observed in these cells .
Head and Neck Cancer Cells
The effect of TA on hypopharyngeal FaDu cancer cells and
YD-38 gingival squamous cell carcinoma was investigated by
Ta et al.  and Darvin et al. , respectively. In FaDu cells
treatment with low dose (25 μM) of TA led to cell cycle arrest
in G2/M phase. As the dose of TA was increased, apoptosis
was induced with the increase of cell population at sub-G1
phase. Both intrinsic and extrinsic cell death pathways were
affected which was demonstrated by the evaluation of the
expressionof various cyclins and poly (ADP-ribose) polymer-
ase (PARP) as well as phosphorylation of kinases of ERK,
AKT and PKB . In gingival squamous cell carcinoma
Curr Pharmacol Rep (2020) 6:28–37 31
YD-38 cells, TA inhibited Jak2/STAT3 pathway by
preventing the expression as well as phosphorylation of its
elements. It was also proved that TA exerted an intense acti-
vation of p21
Waf 1 /C i p 1
,and p53 genes confirming its
role in G1 phase inhibition .
Liver Cancer Cells
The effect of TA on liver cancer cells was investigated in
human hepatoma cell line HepG2. The results of our study
showed activation of Nrf2/ARE signaling pathway as a result
of the treatment with 2 and 10 μM of TA. Subsequent induc-
tion of phase II enzymes, particularly GST, as well as antiox-
idant enzymes, was observed . In contrast, recent study of
Mhlanga et al.  showed increased levels of reactive oxy-
gen species (ROS) and reactive nitrogen species [RNS] and
down-regulation of antioxidant enzymes expression as a result
of the treatment with IC
concentrations of TA, i.e.,
29.4 and 14.7 μM, thus significantly higher than that applied
in our study. The results of both studies confirm earlier sug-
gestions  that TA may act as antioxidant or pro-oxidant
depending on concentration. On the other hand, GSTTwhich
was induced by TA in our study acts as a scavenger of elec-
trophiles, such as epoxides. However, it may also metaboli-
cally activate halogenated compounds, thus producing a vari-
ety of intermediates that can potentially damage DNA and
cells . Therefore, its induction in cancer cells might be
considered as ambiguous. Moreover, in another study, TA
isolated from Caesalpinia coriaria induced G2/M phase cell
cycle arrest and triggered cell death by microtubule stabiliza-
tion in human hepatoma Hep3B cells .
Colon Cancer Cells
Interesting mechanism of inhibition of colorectal cancer
cells (CRC) proliferation was proposed by Yang et al.
[39••]. This group demonstrated that TA inhibits pyru-
vate kinase PKM2 activity and subsequently suppresses
cell proliferation. They proposed, as an underlying
mechanism of enzyme inhibition, binding of TA to ly-
sine residue 433, which triggers the dissociation of
PKM2 tetramers and blocks the activity of PKM2, not
affecting PKM1 isozyme. The non-allosteric isoform
PKM1 is constitutively active, and expressed in termi-
nally differentiated tissues. By contrast, PKM2 is
expressed in tissues with anabolic functions, and is sub-
ject to complex allosteric regulation. In the majority of
cancer cells, the expression of PKM2 is increased,
which suggests that PKM2 may be an attractive target
for cancer therapy . Therefore, TA might be consid-
ered as one of the molecules acting as PKM2 inhibitor.
Glioma Cancer Cells
The effect of TA was studied in rat C6 and human T98G
glioma cell lines and verified in glioblastoma rat model. In
our study, no significant differences in cell cycle distribution
was observed in C6 glioma cells, but in T98G increased num-
ber of cells in S phase was found after incubation with TA at
the concentrations lower and higher than IC
. In both cell
lines, TA significantly increased the number of dead cells.
Induction of apoptosis resulted mostly from increased level
of caspase-3 . In contrast, in the report of Bona et al.
, the increased sub-G1 population of C6 cells, as a result
of the treatment with TA in comparable concentrations, was
described, along with the induction of apoptosis and necrosis.
Moreover, TA reduced the formation and size of colonies, as
well as cell migration and adhesion. Importantly, anti-glioma
effect was also observed in vivo. TA decreased tumor volume
and increased the area of intra-tumoral necrosis and infiltra-
tion of lymphocytes without damage of the surrounding tis-
sue. These data suggest that TA may potentially support the
therapy of these highly aggressive tumors.
As the examples above show, TA may inhibit proliferation
and enhance, via different mechanisms, cell death of various
cancer cells. However, so far, the similar data on normal cells
or immortalized normal cells are scarce.
The Cellular Effect of Tannic Acid
Beyond Cancer Cell Death and Proliferation
Epithelial-to-mesenchymal transition (EMT) is a dynamic,
self-controlled, physiological process by which epithelial cells
lose their junctional architecture and apical-basal polarity, de-
tach from each other, and convert into a mesenchymal pheno-
type [43,44]. EMT is crucial during embryogenesis, wound
healing, and tissue regeneration; however, in noncontrolled
conditions, it may lead to fibrosis, angiogenesis, and tumor
progression with metastatic expansion . It has recently
been reported that TA treatment prevents TGFβ-induced
EMT in breast cancer cells as well as in lung epithelial cells
[46••,47]. The direct interaction between TA and TGF-β1
was observed, attenuating the TGF-βsignaling . In lung
epithelial cells, TA also decreased the expression of N-
cadherin, type-1-collagen, fibronectin, and vimentin.
Additionally, phosphorylation of Smad2 and 3, Akt,
ERK1/2, JNK1/2, and p38 also decreased after the treatment
with TA [47,48]. Moreover, in breast cancer cell line model,
TA not only led to EMT inhibition, but also prevented the
TGFβ-induced increase in cancer stem cells (CSC) formation.
Stemness-marker expression, including ALDH1 activity and
ratio was also decreased after the treat-
ment with only 10 μMTA[46••]. Moreover, TA attenuated
NF-κB signaling which is regarded as one of the most
32 Curr Pharmacol Rep (2020) 6:28–37
important mechanisms leading to the alleviation of CSC for-
mation and EMT [46••]. In addition, blocking of NF-κBsig-
naling by TA in bone marrow–derived macrophages inhibited
NLRP3 inflammasome activation . Recent data suggests
that excessive NLRP3 inflammasome activation characterizes
different cancer cells including head and neck squamous cell
carcinoma and colorectal cancer cells. In U87 and GL261
xenograft mouse GBM model, NLRP3 inflammasome was
involved in the resistance to radiotherapy . Thus TA, by
inhibiting NLRP3, may reduce cancer cell survival or improve
the outcome of therapy.
The antiangiogenic properties of TA along with migration
inhibition of MDA-MB-231 breast cancer cells were tested in
the early study of Chen et al. . TA inhibited cell migration
induced by chemokine CXCL12. The effect of TA on the
angiogenic consequences of CXCL12/CXCR4 interaction
was studied using an in vitro assay of capillary tube out-
growth. Treatment with 0.5 g/ml of TA completely inhibited
tube formation induced by CXCL12, but not by basic fibro-
blast growth factor (bFGF) or endothelial cell growth supple-
ment (ECGS) in bovine aortic endothelial cells (BAEC), sug-
gesting that TA selectively antagonized the angiogenic activ-
ity of CXCL12. Chemokines, such as CXCL12 and their re-
ceptors, are now increasingly recognized as critical communi-
cation bridges between tumor cells and stromal cells to create
a permissive microenvironment for tumor growth and metas-
tasis . Thus, both observations deserve further studies, but
so far were not continued.
Attempts to Apply Tannic Acid for Cancer
Cells Sensitization and Overcoming Multidrug
The treatment of cancer with chemotherapeutic agents has two
major problems, time-dependent development of tumor resis-
tance to therapy and nonspecific toxicity toward normal cells.
A growing amount of studies indicate that plant polyphenols,
including TA, are able to sensitize drug-resistant tumors to
chemotherapy via various mechanisms, as well as to be pro-
tective from therapy-associated toxicities [53•]. One of the
intracellular targets of polyphenols may be the proteasome.
This proteolytic enzyme complex, responsible for intracellular
protein degradation has been shown to play an important role
in tumor growth and the development of drug resistance.
Thus, inhibition of proteasome is considered as one of the
mechanisms to overcome drug resistance and chemosensitize
cancer cells to chemotherapy . The ability of TA to inhibit
the proteasome activity was tested and verified in purified 20S
proteasome and cellular 26S proteasome in different cell types
as well as in tumor-bearing mouse models. Inhibition of the
proteasome function by TA resulted in increased p27 and Bax
expression, and impaired cell cycle progression .
However, no combination with anticancer drugs was tested
in this system.
Poly (ADP-ribose) glycohydrolase (PARG) is the main nucle-
ar enzyme, which digests poly (ADP-ribose) into ADP-ribose.
PARG inhibitors could also be considered as chemotherapeutic
agents, because of its involvement in DNA repair . TA was
found to be PARG inhibitor, and through this mechanism, the
sensitivity of ovarian carcinoma cells to cisplatin was increased.
Combined treatment with TA and cisplatin induced apoptosis
and increased DNA damage in the human ovarian carcinomas
–cisplatin-resistant SKOV-3 CDDP/R cell line and cisplatin-
sensitive SKOV-3 cell line .
The main mechanism leading to the multidrug resistance
(MDR) after the treatment with anticancer drugs is the over-
expression of ABC transporters in cancer cells. Among ABC
transporters, the major target of potential chemosensitizers is
P-glycoprotein (P-gp; MDR-1) . P-gp is expressed in var-
ious cancers and mediates MDR by actively transporting a
wide range of anticancer drugs, including doxorubicin [59•].
Early report of Naus et al.  described interactions between
TA and chemotherapeutic drugs in malignant human
cholangiocytes. TA inhibited cellular efflux pathways, as de-
termined by calcein retention assays by decreasing the expres-
sion of P-gp, MRP1, and MRP2 membrane efflux pumps.
Modulation of drug efflux pathways resulted in synergistic
effect to mitomycin C and 5-fluorouracil used in cholangio-
In more recent study, the P-gp overexpressing human colon
cancer cell line Caco-2 and human T-lymphoblastic leukemia
cell line CEM/ADR 5000 were used to evaluate the effect of
TA combination with doxorubicin (DOX). This combination
synergistically sensitized both types of cells to the treatment.
Decreased activity of P-gp as a result of the treatment with TA
indicated that the inhibition of this protein is responsible for
chemosensitization effect . DOX is a highly effective drug,
but its toxicity to normal cells, particularly, cardiomyocytes,
restricts its therapeutic application. Thus, the use of phyto-
chemicals as a protective tactic to reverse DOX-induced
cardiotoxicity was the subject of several studies . Zhang
et al.  reported that pretreatment of rats with TA weakened
DOX-induced cardiotoxicity by inhibiting oxidative stress, in-
flammation, and apoptotic damage. The possible protection of
normal human oral keratinocytes against DOX-induced cyto-
toxicity without mitigating its cytotoxic potential against oral
cancer cells was investigated in normal human oral
keratinocytes and HSC-2 human oral squamous cell carcinoma
cells. TA at the concentration above 50 μM mitigated the
DOX-induced keratinocyte toxicity without weakening DOX
effect in SSC cells. In contrast, combination of TA at the
concentration of 50 μM and 100 μMwithDOXalmost
completely inhibited their survival . The above data indi-
cate that TA may be considered as a potential adjuvant in
Curr Pharmacol Rep (2020) 6:28–37 33
Tannic Acid as a Carrier of Anticancer Drugs
Nanomedical approaches to drug delivery aim at developing
nanoscale particles or molecules to improve drug bioavailability
both at specific places in the body and over a period of time.
Different approaches have been applied to effectively load target
drugs to enhance delivery resulting in increasing number of
nanoparticles being carriers of anticancer drugs [64••]. Recently
TA attracted attention as a useful excipient for generation of
drug-loaded nanoparticles. TA, being an additive molecule, can
improve solubilization of various hydrophobic drugs intended
for parenteral applications. TA possesses additive feature due to
its low viscosity, good water solubility, and biocompatibility. TA
can bind to drug molecules via hydrophobic interactions, which
in turn form a self-assembled cross-linked network . Such
approach was used to generate TA –paclitaxel (PTX) self-
assembly nanoparticles (TAP NPs) in order to potentiate PTX
chemotherapeutic efficiency. The TAP NPs efficiently internal-
ized into the cytoplasm of breast cancer MDA-MB-231 cells
bition of cells proliferation, clones formation, and migration.
Moreover, TAP NPs increased beta-tubulin stabilization and ap-
optosis and limited P-gp-mediated drug efflux . Moreover,
the study of PTX administered in a form of PTX-loaded tannic
acid/poly(N-vinylpyrrolidone) nanoparticles (PTX-NP) showed
that TA exhibits P-gp inhibitory function, whereas the intestinal
retention of a drug is prolonged and trans-epithelial transport
properties are improved. Oral administration of PTX-NP gener-
ated a high oral delivery efficiency and relative oral bioavailabil-
ity of 25.6% in rats, and further displayed a significant tumor-
inhibition effect in a xenograft breast tumor model. These find-
ings confirmed that PTX-NP might be a promising oral drug
formulation for chemotherapy .
In another study, an injectable drug delivery system was de-
veloped, involving oxaliplatin (OXA) and TA incorporated into
polymeric nanoparticles in a form of a thermo-sensitive hydrogel,
(OXA/TA NPs-H). Intraperitoneal application of OXA/TA NPs-
H restricted the growth of CT26 peritoneal colon cancer in vivo,
improved the quality of life, and prolonged the survival time of
the model mice, which suggests this drug delivery system can be
applied in colorectal cancer treatment .
Another form of nanoparticles with TA was formed by co-
assembling TA and polymer poly (2-oxazoline) and DOX as a
model drug . These polymeric nanoparticles showed high sta-
bility, good biocompatibility, and the cellular uptake. Thus, they
can be considered as promising drug carriers for cancer therapy.
The major challenge in the design of anticancer drug carrier
is the drug release in response to tumor-specific microenvi-
ronments (TMEs) such as low pH, abnormal levels of ROS,
and hypoxic conditions [69–72]. Hyaluronic acid, abundant in
synovial fluid and the extracellular matrix, owing specific
binding affinity for CD44-overexpressing cancer cells, has
been used to prepare amphiphilic derivatives, capable of
self-assembling into the nano-sized particles. However, these
nanoparticles (HANPs) were unstable in physiological condi-
tions and released a significant amount of drug into the blood-
stream. This problem has been overcome by preparing metal
)-phenolic (TA) network (MPN)-coated HANPs (MPN-
HANPs) as a pH-sensitive nano-carrier for hydrophobic
drugs. DOX-loaded MPN-HANPs exhibited a higher cy-
totoxicity for the squamous cell carcinoma (SCC7), sug-
gesting their potential use as a drug carrier in targeted
cancer therapy [73••].
Interesting application of TA in the treatment of lung can-
cer was described by Hatami et al. , who examined the TA
interaction with the lung fluid (LF) –the major barrier for the
distribution of drugs to the lungs. They demonstrated that TA
binds to LF and forms self-assemblies, which profoundly en-
hance interaction with lung cancer cells. Thus, TA itself may
be considered as a novel carrier for pharmaceutical drugs such
as gemcitabine, carboplatin, and irinotecan. Therefore, TA,
when used to formulate effective, yet nontoxic anticancer
nanoparticles with drugs, has an excellent potential for trans-
lation from the bench to bedside cancer therapy.
TA showed up to be more versatile molecule than was initially
thought. While the earliest investigations’concern was TA
chemopreventive potential related to its ability to inhibit car-
cinogenesis initiation and promotion in animal models, over
the years, the knowledge of its biological activities extended
beyond this aspect. It was demonstrated that TA may interfere
with the mechanisms, which might be important for cancer
therapy, e.g. prevention of EMT or decrease in CSC forma-
tion. Moreover, available data indicate that TA may increase
cancer cells sensitization to anticancer drugs and can help over-
coming multidrug resistance. However, TA chemosensitization
properties require more profound research on its effect on non-
tumorigenic cells. In addition, TA can be useful excipient for
generation of drug-loaded nanoparticles. Therefore, TA
certainly deserves further studies.
Funding Information This work is based upon work from COSTAction
NutRedOx-CA16112 supported by COST (European Cooperation in
Science and Technology).
Compliance with Ethical Standards
Conflict of Interest The authors received no financial support in the
writing of this manuscript.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
34 Curr Pharmacol Rep (2020) 6:28–37
Open Access This article is licensed under a Creative Commons
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