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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, TA was 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.
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Tannic Acid: Specific Form of Tannins in Cancer Chemoprevention
and Therapy-Old and New Applications
Wanda Baer-Dubowska
1
&Hanna Szaefer
1
&Aleksandra Majchrzak-Celińska
1
&Violetta Krajka-Kuźniak
1
Published online: 27 March 2020
Abstract
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
Introduction
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 [1].
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 [2].
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 212 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
baerw@ump.edu.pl
1
Department of Pharmaceutical Biochemistry, Poznan University of
Medical Sciences, Święcicki 4 Str, Poznań,Poland
Current Pharmacology Reports (2020) 6:2837
https://doi.org/10.1007/s40495-020-00211-y
REDOX MODULATORS (C JACOB, SECTION EDITOR)
#The Author(s) 2020
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
acs/en/molecule-of-the-week/archive/t/tannic-acid.html]. As
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 [3].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 [4]. 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 [11]. However, it can act also
as pro-oxidant resulting in oxidative DNA damage [12].
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
therapy.
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 [13]. 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
and progression
Induction of cell cycle arrrest
and apoptosis of cancer cells
Inhibition of cancer cells
migration, invasion and
colony formation
Modulation of phase I and II drug
metabolizin
g
enz
y
mes
Inhibition of cancer cell
proliferation and
angiogenesis
Inhibition of epithelial-to-
mesenchymal transition
Chemosenstization and impact
on multidrug resistance
An element of anti-cancer drug
delivery systems/carrier of anti-
cancer drugs
Fig. 1 The overview of mechanisms exerted by tannic acid important for cancer chemoprevention and/or therapy
Curr Pharmacol Rep (2020) 6:2837 29
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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 [1517]. 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 [19].
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 [16].
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 [15].
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 [13]. 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 [20]. 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 [13]. 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 [20]. 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 [21].
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 [22].
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 [23]. Anti-inflammatory activity of TA was
also shown in the context of house dust miteinduced atopic
Chemical, physical, biological
carcinogen
INITIATION PROMOTION PROGRESSION
Normal cells
Genetically and/or
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) 6:2837
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
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 [25]. However, signifi-
cant hepatoprotective effects against acetaminophen-induced
hepatotoxicity were recently described [26]. 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
Cancer Cells
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. [32] performed a series of experiments in which
ER-positive breast cancer cells, MCF7, and triple negative
(ER
,PR
,HER2
) 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. [30]. 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 [31]. 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 [32].
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 [33].
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. [34] and Darvin et al. [35], 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 [34]. In gingival squamous cell carcinoma
Curr Pharmacol Rep (2020) 6:2837 31
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
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
,p27
Kip1
,and p53 genes confirming its
role in G1 phase inhibition [35].
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 [36]. In contrast, recent study of
Mhlanga et al. [37] 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
50
and IC
25
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 [12] 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 [36]. 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 [38].
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 [40]. 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
50
. In both cell
lines, TA significantly increased the number of dead cells.
Induction of apoptosis resulted mostly from increased level
of caspase-3 [41]. In contrast, in the report of Bona et al.
[42], 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 [45]. 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 [47]. 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
the CD44
high
/CD24
low
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) 6:2837
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
important mechanisms leading to the alleviation of CSC for-
mation and EMT [46••]. In addition, blocking of NF-κBsig-
naling by TA in bone marrowderived macrophages inhibited
NLRP3 inflammasome activation [49]. 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 [50]. 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. [51]. 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 [52]. Thus, both observations deserve further studies, but
so far were not continued.
Attempts to Apply Tannic Acid for Cancer
Cells Sensitization and Overcoming Multidrug
Resistance
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 [54]. 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 [55].
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 [56]. 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 [57].
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) [58]. 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. [60] 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-
carcinoma therapy.
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 [58]. 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 [61]. Zhang
et al. [62] 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 [63]. The above data indi-
cate that TA may be considered as a potential adjuvant in
cancer chemotherapy.
Curr Pharmacol Rep (2020) 6:2837 33
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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 [67]. 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
resultinginincreased,incomparisonwithpaclitaxelalone,inhi-
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 [65]. 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 [66].
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 [67].
Another form of nanoparticles with TA was formed by co-
assembling TA and polymer poly (2-oxazoline) and DOX as a
model drug [68]. 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 [6972]. 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
(Fe
3+
)-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. [74], 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.
Conclusions
TA showed up to be more versatile molecule than was initially
thought. While the earliest investigationsconcern 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
the authors.
34 Curr Pharmacol Rep (2020) 6:2837
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Open Access This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing, adap-
tation, distribution and reproduction in any medium or format, as long as
you give appropriate credit to the original author(s) and the source, pro-
vide a link to the CreativeCommons licence, and indicate if changes were
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... Phytochemicals such as tannins have been reported to induce cell cycle arrest, cell death, and inhibit the proliferation of various cancer cells including breast, prostate, liver, and colon cancer by interfering with signaling cascades involved in cell survival and apoptotic pathways (Baer-Dubowska et al., 2020). The condensed tannins such as proanthocyanidins are major constituents of fruits such Functional profiling of Achillea fragrantissima as apple; these are also found to be major constituents of beverages such as coffee and tea. ...
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Chemoprevention with alternative approaches is emerging as a significant component of therapeutic regimen for the management of various diseases in human population including cancer. The concept of personalized nutrition is attracting considerable interest as an effective and affordable strategy in the prevention of chronic diseases. It is acknowledged that diet-derived agents or non-dietary natural products are not only the source of traditional medicines but also the lead compounds for currently used pharmaceuticals with excellent efficacy against a number of human diseases. Achillea species (Asteraceae) are considered as functional foods, which are important constituents of traditional medicine and commonly consumed as herbal tea or food additives worldwide. The studies presented herein demonstrate the effects of the hydro-methanolic extract of A. fragrantissima against a panel of cancer cells that include breast cancer (MDA-MB-231,MCF-7,SKBR3), pancreatic cancer (BxPC-3, MiaPaCa-2), prostate cancer (LNCaP,C4-2B,PC-3), and lung cancer (A549). The experimental results presented in the study show that the extract, which is rich in structurally diverse phytochemicals, effectively inhibits the cell growth and induces apoptotic cell death in human cancer cells. The treatment of the cancer cells with the extract resulted in a progressive decrease in cell migration and invasiveness, demonstrating an effective anti-metastatic activity. The mechanism by which the extract exerts its effects against cancer cells potentially engages NF-κB signaling and downregulation of its target cytokines such as VEGF. The study provides evidence that partially support the importance of functional foods and highlights their significance in disease prevention.
... 202 The effect of TA on cell viability and proliferation is dependent on cell type and its interaction with TA, the dose of TA, and its release rate. 364 The degradation rate and resistance against deformation during new tissue formation of biomedical scaffolds is another essential factor in tissue engineering. Functional groups and structure of base materials and medium temperature and pH could affect the degradation rate. ...
Article
Tannic acid (TA), a natural polyphenol, is a hydrolysable amphiphilic tannin derivative of gallic acid with several galloyl groups in its structure. Tannic acid interacts with various organic, inorganic, hydrophilic, and hydrophobic materials such as proteins and polysaccharides via hydrogen bonding, electrostatic, coordinative bonding, and hydrophobic interactions. Tannic acid has been studied for various biomedical applications as a natural crosslinker with anti-inflammatory, antibacterial, and anticancer activities. In this review, we focus on TA-based hydrogels for biomaterials engineering to help biomaterials scientists and engineers better realize TA's potential in the design and fabrication of novel hydrogel biomaterials. The interactions of TA with various natural or synthetic compounds are deliberated, discussing parameters that affect TA-material interactions thus providing a fundamental set of criteria for utilizing TA in hydrogels for tissue healing and regeneration. The review also discusses the merits and demerits of using TA in developing hydrogels either through direct incorporation in the hydrogel formulation or indirectly via immersing the final product in a TA solution. In general, TA is a natural bioactive molecule with diverse potential for engineering biomedical hydrogels.
... The derivatives of betalamic acid, xanthohumol, betalains, and tannins have been explored to a lesser degree; nonetheless, they do exhibit efficacy in modulating Nrf2 [48]. Tannic acid has been shown in vitro to increase the expression of phase II enzymes downstream of Nrf2 [49]. Betanin was explored in hepatoma-derived HepG2 cell lines in hepatic cancer, showing anticarcinogenic and hepatoprotective effects by Nrf2 activation [50], consistent with findings with xanthohumol. ...
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Kaempferol is a natural flavonoid, which has been widely investigated in the treatment of cancer, cardiovascular diseases, metabolic complications, and neurological disorders. Nrf2 (nuclear factor erythroid 2-related factor 2) is a transcription factor involved in mediating carcinogenesis and other ailments, playing an important role in regulating oxidative stress. The activation of Nrf2 results in the expression of proteins and cytoprotective enzymes, which provide cellular protection against reactive oxygen species. Phytochemicals, either alone or in combination, have been used to modulate Nrf2 in cancer and other ailments. Among them, kaempferol has been recently explored for its anti-cancer and other anti-disease therapeutic efficacy, targeting Nrf2 modulation. In combating cancer, diabetic complications, metabolic disorders, and neurological disorders, kaempferol has been shown to regulate Nrf2 and reduce redox homeostasis. In this context, this review article highlights the current status of the therapeutic potential of kaempferol by targeting Nrf2 modulation in cancer, diabetic complications, neurological disorders, and cardiovascular disorders. In addition, we provide future perspectives on kaempferol targeting Nrf2 modulation as a potential therapeutic approach.
... In human studies, the anticancer properties of tannins have been investigated, finding interesting results, particularly for tannic acid, both in cancer prophylaxis and as an adjuvant in cancer therapy [134,135]. Tannic acid has also shown promising antibacterial activity against both Gram-positive and Gram-negative species, such as S. aureus, E. coli, Streptococcus pyogenes, Enterococcus faecalis, P. aeruginosa, Yersinia enterocolitica and Listeria innocua [136][137][138]. Furthermore, it has shown antiviral effects against pathogenic viruses such as influenza A virus, Papilloma virus, noroviruses, Herpes simplex virus type 1 and 2 and HIV [139]. ...
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Nutraceuticals have been receiving increasing attention in the last few years due to their potential role as adjuvants against non-communicable chronic diseases (cardiovascular disease, diabetes, cancer, etc.). However, a limited number of studies have been performed to evaluate the bioavailability of such compounds, and it is generally reported that a substantial elevation of their plasma concentration can only be achieved when they are consumed at pharmacological levels. Even so, positive effects have been reported associated with an average dietary consumption of several nutraceutical classes, meaning that the primary compound might not be solely responsible for all the biological effects. The in vivo activities of such biomolecules might be carried out by metabolites derived from gut microbiota fermentative transformation. This review discusses the structure and properties of phenolic nutraceuticals (i.e., polyphenols and tannins) and the putative role of the human gut microbiota in influencing the beneficial effects of such compounds.
... Tannic acid was also studied for its possible application in cancer prophylaxis and adjuvant cancer therapy [47]. Many anti-carcinogenic properties of tannic acid were highlighted, reporting that-it can exert anti-carcinogenic effects via its anti-oxidant and anti-inflammatory effects, it can exert an anti-mutagenic and anti-tumorigenic effect, it can reduce several cancerous properties of cancer cell lines. ...
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Anti-nutrients are the biomolecules that if present in food along with nutrients, can reduce either the absorption or the utilization of nutrients. The physiological importance of anti-nutrients is been debated for a long time because the researches point at different effects on different anti-nutrients in foods. Some anti-nutrients show both beneficial and harmful physiological effects that depend on molar ratios between nutrients and anti-nutrients and some other factors. Previous studies suggested that anti-nutrients if are consumed in a healthy amount they may act as a useful natural drug to ameliorate human health. They can have physiological importance in the nutrition of the organism. In this review, we compiled the beneficial attributes of major plant-based anti-nutrients to improve health conditions, along with their potential adverse effects.
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The ingestion of hydrolysable tannins as a potential nutrient to reduce boar odor in entire males results in the significant enlargement of parotid glands (parotidomegaly). The objective of this study was to characterize the effects of different levels of hydrolysable tannins in the diet of fattening boars (n = 24) on salivary gland morphology and proline-rich protein (PRP) expression at the histological level. Four treatment groups of pigs (n = 6 per group) were fed either a control (T0) or experimental diet, where the T0 diet was supplemented with 1% (T1), 2% (T2), or 3% (T3) of the hydrolysable tannin-rich extract Farmatan®. After slaughter, the parotid and mandibular glands of the experimental pigs were harvested and dissected for staining using Goldner’s Trichrome method, and immunohistochemical studies with antibodies against PRPs. Morphometric analysis was performed on microtome sections of both salivary glands, to measure the acinar area, the lobular area, the area of the secretory ductal cells, and the sizes of glandular cells and their nuclei. Histological assessment revealed that significant parotidomegaly was only present in the T3 group, based on the presence of larger glandular lobules, acinar areas, and their higher nucleus to cytoplasm ratio. The immunohistochemical method, supported by color intensity measurements, indicated significant increases in basic PRPs (PRB2) in the T3 and acidic PRPs (PRH1/2) in the T1 groups. Tannin supplementation did not affect the histo-morphological properties of the mandibular gland. This study confirms that pigs can adapt to a tannin-rich diet by making structural changes in their parotid salivary gland, indicating its higher functional activity.
Article
Numerous flame retardants (FRs) have been researched since the 1900s to improve the fire-resistance performance of materials used in construction, industrial production, and daily life, which have developed significantly over the past 25 years. Especially, biomolecules have recently attracted significant attention as green flame retardants (FRs) owing to their low environmental and general toxicological impacts and rapidly decreasing cost. In particular, many flame-retardant biomolecules can promote char formation by swelling upon heating owing to their abundant carbon-, phosphorus-, and nitrogen-containing functional groups. In this review, we focus on several types of biomolecules that have been applied as FRs. We classify most of the biomolecules reported in FR applications to date, such as carbohydrate- and biomass-derived molecules, proteins, DNA, phytic acid, and ATP. In addition, we describe and summarize the unique properties of these materials that make them suitable for use as FRs. Furthermore, we discussed the past and present status of biomolecular FRs and interpreted some of the challenges that need to be addressed in order for biomolecules to be widely used as next-generation FRs. We believe that this review will promote the research and development of the next-generation FRs having environmental and biological compatibility.
Article
Introduction : The significance of the crosstalk between pro-inflammatory mediators and carcinogenesis is widely discussed. These mediators play decisive roles at different stages of tumor development, including initiation, promotion, and metastasis. Arum palaestinum Boiss., Ocimum basilicum L., and Trigonella foenum-graecum L. and their crude extracts are traditionally used in the Arab and Islamic herbal medicine to treat a variety of cancers and inflammatory illnesses. Methods : Human monocytic cell line (THP-1)-derived macrophages were used to evaluate anti-inflammatory, cytotoxic, and cytostatic effects of the ethanolic plant extracts. Cytotoxic and cytostatic effects were measured with the MTT assay. In addition, the production levels of pro-inflammatory mediators (TNF-α, IL-6, and nitric oxide) and anti-inflammatory cytokine (IL-10) were measured in lipopolysaccharide (LPS)-activated THP-1-derived macrophages in the absence and presence of increasing concentrations of the three plant extracts. Results : The three plant extracts suppressed the production of NO and TNF-α and IL-6, and enhanced the production of IL-10 in LPS-activated THP-1-derived macrophages. In addition, these extracts inhibited the growth of THP-1-derived macrophages in a concentration-dependent manner at non-toxic concentrations. T. foenum-graecum exhibited the highest cytostatic effects with an IC50 of 512 µg/ mL compared to O. basilicum (no cytostatic effects) and A. palaestinum (IC50=1274 µg/mL). Conclusion : Even though more studies are needed to elucidate the mechanisms of observed cytostatic and anti-inflammatory effects, to some extent, these effects could be attributed to the flavonoids, phenolic compounds, and tannin content detected in the plants’ extracts.
Article
Colorectal cancer is the third most common malignancy that leads to significant mortality around the world. Chronic colonic inflammation could induce a protumor effect by the massive release of pro-inflammatory cytokines, facilitating migration, invasion, and metastasis of malignant cells in colorectal cancer. Therefore, developing a combination regimen of anti-inflammation and antitumor therapies is a promising strategy for the treatment of colorectal cancer. Here, we report that tannic acid-containing nanoparticles, formed by a turbulent-mixing technique, have exhibited uniform size, high stability, and pH-triggered drug release in the gastrointestinal tract, and could overcome intestinal mucosa for drug delivery in the colorectal region. As a drug carrier itself, with potent antioxidant and anti-inflammatory properties, tannic acid-containing nanoparticles showed great therapeutic effect in preventing the development of colitis-associated colorectal cancer (CAC) through oral administration. Furthermore, we used a therapeutic nanocarrier to deliver chemotherapeutic drugs for CAC treatment, generating lower systemic toxicity and superior antitumor performance through concurrent anti-inflammation and antitumor treatment. As a result, we confirmed that the drug carrier itself with therapeutic function could improve the overall therapeutic performance, and provided a safe and effective tannic acid-containing nanoplatform for the prevention and treatment of colon diseases.
Article
Breast cancer is the most common malignancy in women and is rated among one of the three common malignancies worldwide in combination with colon and lung cancer. The escalating mortality rate of breast cancer patients has captivated the attention of the present-day researchers to come up with new management options. According to WHO, early detection, timely diagnosis and comprehensive breast cancer management are the three cornerstones for controlling breast cancer incidences per year. Multidisciplinary theragnostic approaches for simultaneous diagnosis and treatment of breast cancer have further enriched the therapeutic arsenal. Imaging and biopsy play a significant role in the diagnosis of breast cancer. The treatment plan mostly initiates with general surgery or radiation therapy followed up with adjuvant and/or neoadjuvant therapy. Conventional chemotherapeutics in breast cancer suffer from toxicity and lack of site specificity. Bio-safe gold nanoparticles hold sufficient promise for bridging this gap. Diverse phytochemicals-based synthesis routes to arrive at nano-dimensional gold with spotlight on reaction mechanisms, reaction variables, specific advantages, toxicity and their influence in breast cancer conditions are the focus of this work. This review marks the first attempt to explore the potential of phytochemical-derived nano-gold in breast cancer treatment.
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The study investigated the cytotoxic effect of a natural polyphenolic compound Tannic acid (TA) on human liver hepatocellular carcinoma (HepG2) cells and elucidated the possible mechanisms that lead to apoptosis and oxidative stress HepG2 cell. The HepG2 cells were treated with TA for 24 h and various assays were conducted to determine whether TA could induce cell death and oxidative stress. The cell viability assay was used to determine the half maximal inhibitory concentration (IC 50), caspase activity and cellular ATP were determined by luminometry. Microscopy was employed to determine deoxyribonucleic acid (DNA) integrity, while thiobarbituric acid (TBARS) and nitric oxide synthase (NOS) assays were used to elucidate cellular reactive oxygen species (ROS) and reactive nitrogen species (RNS), respectively. Western blotting was used to confirm protein expression. The results revealed that tannic acid induced caspase activation and increased the presence of cellular ROS and RNS, while downregulating antioxidant expression. Tannic acid also showed increased cell death and increased DNA fragmentation. In conclusion, TA was able to induce apoptosis by DNA fragmentation via caspase-dependent and caspase-independent mechanism. It was also able to induce oxidative stress, consequently contributing to cell death.
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Although self-assembled nanoparticles (SNPs) have been used extensively for targeted drug delivery, their clinical applications have been limited since most of the drugs are released into the blood before they reach their target site. In this study, metal-phenolic network (MPN)-coated SNPs (MPN-SNPs), which consist of an amphiphilic hyaluronic acid derivative, were prepared to be a pH-responsive nanocarrier to facilitate drug release in tumor microenvironments (TME). Due to their amphiphilic nature, SNPs were capable of encapsulating doxorubicin (DOX), chosen as the model anticancer drug. Tannic acid and FeCl3 were added to the surface of the DOX-SNPs, which allowed them to be readily coated with MPNs as the diffusion barrier. The pH-sensitive MPN corona allowed for a rapid release of DOX and effective cellular SNP uptake in the mildly acidic condition (pH 6.5) mimicking TME, to which the hyaluronic acid was exposed to facilitate receptor-mediated endocytosis. The DOX-loaded MPN-SNPs exhibited a higher cytotoxicity for the cancer cells, suggesting their potential use as a drug carrier in targeted cancer therapy.
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Glioblastoma is a devastating tumor affecting the central nervous system with infiltrative capacity, high proliferation rate and chemoresistance. Therefore, it is urgent to find new therapeutic alternatives that improve this prognosis. Herein, we focused on tannic acid (TA) a polyphenol with antioxidant and antiproliferative activities. In this work, the antitumor and antioxidant effects of TA on rat (C6) glioblastoma cells and their cytotoxicity relative to primary astrocyte cultures were evaluated in vitro. Cells were exposed to TA of 6.25 to 75 μM for 24, 48 and/or 72 h. In addition, colony formation, migration and cell adhesion were analyzed and flow cytometry was used to analyze cell death and cell cycle. Next, the action of TA was evaluated in a preclinical glioblastoma model performed on Wistar rats. In this protocol, the animals were treated with a dose of 50 mg/kg/day TA for 15 days. Our results demonstrated that TA induced in vitro selective antiglioma activity, not demonstrating cytotoxicity in astrocyte culture. It induced cell death by apoptosis and cell cycle arrest, reducing formation and size of colonies, cell migration/adhesion and showing to be a potential antioxidant. Interestingly, the antiglioma effect was also observed in vivo, as TA decreased tumor volume by 55%, accompanied by an increase in the area of intratumoral necrosis and infiltration of lymphocytes without causing systemic damage. To the best of our knowledge, this is the first study to report TA activity in a GBM preclinical model. Thus, this natural compound is promising as a treatment for glioblastoma.
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Cancer stem cells (CSCs) are innately resistant to standard therapies, which positions CSCs in the focus of anti-cancer research. In this study, we investigated the potential inhibitory effect of tannic acid (TA) on CSCs. Our data demonstrated that TA (10 μM), at the concentration not inhibiting the proliferation of normal mammary cells (MCF10A), inhibited the formation and growth of mammosphere in MCF7, T47D, MDA-MB-231 cells shown as a decrease in mammosphere formation efficiency (MFE), cell number, diameter of mammosphere, and ALDH1 activity. NF-κB pathway was activated in the mammosphere indicated by an up-regulation of p65, a degradation of IκBα, and an increased IL-6. The inhibition of NF-κB pathway via gene silencing of p65 (sip65), NF-κB inhibitor (PDTC), or IKK inhibitor (Bay11-7082) alleviated MFE. Other CSCs markers such as an increase in ALDH1 and CD44high/CD24low ratio were ameliorated by sip65. TA also alleviated TGFβ-induced EMT, increase in MFE, and NF-κB activation. In murine xenograft model, TA reduced tumor volume which was associated with a decrease in CD44high/CD24low expression and IKK phosphorylation. These results suggest that TA negatively regulates CSCs by inhibiting NF-κB activation and thereby prevents cancer cells from undergoing EMT and CSCs formation, and may thus be a promising therapy targeting CSCs.
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Epithelial-to-mesenchymal transition (EMT) is a self-regulated physiological process required for tissue repair that, in non-controled conditions may lead to fibrosis, angiogenesis, loss of normal organ function or cancer. Although several molecular pathways involved in EMT regulation have been described, this process does not have any specific treatment. This article introduces a systematic review of effective natural plant compounds and their extract that modulates the pathological EMT or its deleterious effects, through acting on different cellular signal transduction pathways both in vivo and in vitro. Thereby, cryptotanshinone, resveratrol, oxymatrine, ligustrazine, osthole, codonolactone, betanin, tannic acid, gentiopicroside, curcumin, genistein, paeoniflorin, gambogic acid and Cinnamomum cassia extracts inhibit EMT acting on transforming growth factor-β (TGF-β)/Smads signaling pathways. Gedunin, carnosol, celastrol, black rice anthocyanins, Duchesnea indica, cordycepin and Celastrus orbiculatus extract downregulate vimectin, fibronectin and N-cadherin. Sulforaphane, luteolin, celastrol, curcumin, arctigenin inhibit β-catenin signaling pathways. Salvianolic acid-A and plumbagin block oxidative stress, while honokiol, gallic acid, piperlongumine, brusatol and paeoniflorin inhibit EMT transcription factors such as SNAIL, TWIST and ZEB. Plectranthoic acid, resveratrol, genistein, baicalin, polyphyllin I, cairicoside E, luteolin, berberine, nimbolide, curcumin, withaferin-A, jatrophone, ginsenoside-Rb1, honokiol, parthenolide, phoyunnanin-E, epicatechin-3-gallate, gigantol, eupatolide, baicalin and baicalein and nitidine chloride inhibit EMT acting on other signaling pathways (SIRT1, p38 MAPK, NFAT1, SMAD, IL-6, STAT3, AQP5, notch 1, PI3K/Akt, Wnt/β-catenin, NF-κB, FAK/AKT, Hh). Despite the huge amount of preclinical data regarding EMT modulation by the natural compounds of plant, clinical translation is poor. Additionally, this review highlights some relevant examples of clinical trials using natural plant compounds to modulate EMT and its deleterious effects. Overall, this opens up new therapeutic alternatives in cancer, inflammatory and fibrosing diseases through the control of EMT process.
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Article
Abstract Inflammasomes are large intracellular multi-protein signalling complexes that are formed in the cytosolic compartment as an inflammatory immune response to endogenous danger signals. The formation of the inflammasome enables activation of an inflammatory protease caspase-1, pyroptosis initiation with the subsequent cleaving of the pro-inflammatory cytokines interleukin (IL)-1β and proIL-18 to produce active forms. The inflammasome complex consists of a Nod-like receptor (NLR), the adapter apoptosis-associated speck-like (ASC) protein, and Caspase-1. Dysregulation of NLRP3 inflammasome activation is involved tumor pathogenesis, although its role in cancer development and progression remains controversial due to the inconsistent findings described. In this review, we summarize the current knowledge on the contribution of the NLRP3 inflammasome on potential cancer promotion and therapy.
Article
Epithelial-to-mesenchymal transition (EMT) is a fundamental developmental process wherein polarized epithelial cells lose their junctional architecture and apical-basal polarity to become motile mesenchymal cells, and there is emerging evidence for its role in propagating tumor dissemination. While many multifaceted nodules converge onto the EMT program, in this review we will highlight the fundamental biology of the signaling schemas that enable EMT. In many cancers, the property of tumor dissemination and metastasis is closely associated with re-enabling developmental properties such as EMT. We discuss the molecular complexity of the tumor heterogeneity in terms of EMT-based gene expression molecular subtypes, and the rewiring of critical signaling nodules in the subtypes displaying higher degrees of EMT can be therapeutically exploited. Specifically in the context of a deadly malignancy such as ovarian cancer where there are no defined mutations or limited biomarkers for developing targeted therapy or personalized medicine, we highlight the importance of identifying EMT-based subtypes that will improve therapeutic intervention. In ovarian cancer, the poor prognosis mesenchymal 'Mes' subtype presents with amplified signaling of the receptor tyrosine kinase (RTK) AXL, extensive crosstalk with other RTKs such as cMET, EGFR and HER2, and sustained temporal activation of extracellular-signal regulated kinase (ERK) leading to induction of EMT transcription factor Slug, underscoring a pathway addiction in Mes that can be therapeutically targeted. We will further examine the emergence of therapeutic modalities in these EMT subtypes and finally conclude with potential interdisciplinary biophysical methodologies to provide additional insights in deciphering the mechanistic and biochemical aspects of EMT. This review intends to provide an overview of the cellular and molecular changes accompanying epithelial-to-mesenchymal transition (EMT) in development and the requisition of this evolutionarily conserved pathway in cancer progression and metastatic disease. Specifically, in a heterogeneous disease such as ovarian cancer lacking defined targetable mutations, the identification of EMT-based subtypes has opened avenues to tailor precision personalized medicine. In particular, using the oncogenic RTK AXL as an example, we will highlight how this classification enables EMT-subtype specific identification of targets that could improve treatment options for patients and how there is a growing need for biophysical approaches to model dynamic processes such as EMT.
Article
Tannic acid, a hydrolysable tannin, exists commonly in food plants. Tannic acid has already been shown various anticancer mechanisms such as inhibiting the proliferation, inducing a higher apoptotic rate and slowing down the metastasis of different cancers. Moreover, tannic acid was reported to reduce the side effects caused by chemotherapeutics on patients. But whether the tannic acid can improve the treatment of oxaliplatin on colorectal carcinomatosis has yet been studied. In this study, we developed an injectable drug delivery system by physical incorporation of oxaliplatin (OXA) and tannic acid (TA) polymeric nanoparticles (OXA/TA NPs) into a thermo-sensitive hydrogel, OXA/TA NPs-hydrogel (OXA/TA NPs-H). The OXA/TA NPs-H was injected into the peritoneal cavity for the treatment of colorectal peritoneal carcinoma. Firstly, a water-in-oil-in-water double-emulsion (w/o/w) method and solvent-evaporation procedure were used in the preparation of the biodegradable OXA/TA NPs. Then, we prepared the biodegradable thermo-sensitive poly(3-caprolactone) (PCL)-10R5-PCL (PCLR) hydrogel with a low critical solution temperature (LCST) which undergoes gelation process at body temperature. Transmission electron microscopy (TEM) showed the spherical profile of OXA/TA NPs. Fourier-transform infrared (FTIR) spectra demonstrated that OXA and TA were both encapsulated into the OXA/TA NPs. In this study, 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. Our study suggested that OXA/TA NPs-H might have potential application in the treatment of colorectal cancer.
Article
Epithelial–mesenchymal transition (EMT) is a cellular programme that is known to be crucial for embryogenesis, wound healing and malignant progression. During EMT, cell–cell and cell–extracellular matrix interactions are remodelled, which leads to the detachment of epithelial cells from each other and the underlying basement membrane, and a new transcriptional programme is activated to promote the mesenchymal fate. In the context of neoplasias, EMT confers on cancer cells increased tumour-initiating and metastatic potential and a greater resistance to elimination by several therapeutic regimens. In this Review, we discuss recent findings on the mechanisms and roles of EMT in normal and neoplastic tissues, and the cell-intrinsic signals that sustain expression of this programme. We also highlight how EMT gives rise to a variety of intermediate cell states between the epithelial and the mesenchymal state, which could function as cancer stem cells. In addition, we describe the contributions of the tumour microenvironment in inducing EMT and the effects of EMT on the immunobiology of carcinomas.