Resveratrol, cancer and cancer stem cells: A review on past to future

Abstract

Cancer remains to be an unresolved medical challenge despite of tremendous advancement in basic science research and clinical medicine. One of the major limitations is due to the side effects of chemotherapy which remains to be palliative without offering any permanent cure for cancer. Cancer stem cells (CSCs) are the subpopulation of cells in tumors that remain viable even after surgery, chemo- and radio-therapy that eventually responsible for tumor relapse. Hence, by eliminating non-stem cancer cells and cancer stem cells from the patient, permanent cure is expected. Phytochemicals have been under the intensive study to target these CSCs effectively and permanently as they do not cause any side effects. Resveratrol (RSV) is one such compound attaining lot of interest in recent days to target CSCs either alone or in combination. RSV has been used by several researchers to target cancer cells in a variety of disease models, however its CSC targeting abilities are under intensive study at present. This review is to summarize the effects of RSV under in vitro and in vivo conditions along with advantages and disadvantages of its uses against cancer cells and cancer stem cells. From the first reports on phytochemical applications against cancer and cancer stem cells in 1997 and 2002 respectively followed by later reports, up to date observations and developments are enlisted from PubMed in this comprehensive review. RSV is shown to be a potential compound having impact on altering the signal transduction pathways in cancer cells. However, the effects are variable under in vitro and in vivo conditions, and also with its use alone or in combination with other small molecules. Past research on RSV is emphasizing the importance of in vivo experimental models and clinical trials with different prospective combinations, is a hope for future promising treatment regimen.

Full text

Resveratrol, cancer and cancer stem cells: A review on past to future
Vasanth K. Bhaskara
a
, Bharti Mittal
b
, Vijaya V. Mysorekar
c
, Nagarathna Amaresh
d
,
Jesus Simal-Gandara
e
,
*
a
Department of Biochemistry-PG, Ramaiah Post Graduate Center, Ramaiah College - RCASC, Bengaluru 560054, India
b
Immuniteit Lab Pvt Ltd., Electronic City, Bengaluru 560024, India
c
Department of Pathology, Ramaiah Medical College &Hospitals (RMCH), Bengaluru 560054, India
d
Department of Biotechnology, Ramaiah Post Graduate Center, Ramaiah College –RCASC, Bengaluru 560054, India
e
Nutrition and Bromatology Group, Department of Analytical and Food Chemistry, Faculty of Food Science and Technology, University of Vigo –Ourense Campus, E32004
Ourense, Spain
ARTICLE INFO
Keywords:
Resveratrol
Cancer
Cancer stem cells
Therapeutic targeting
Signal transduction
Resistance
In vitro and in vivo studies
ABSTRACT
Cancer remains to be an unresolved medical challenge despite of tremendous advancement in basic science
research and clinical medicine. One of the major limitations is due to the side effects of chemotherapy which
remains to be palliative without offering any permanent cure for cancer. Cancer stem cells (CSCs) are the sub-
population of cells in tumors that remain viable even after surgery, chemo- and radio-therapy that eventually
responsible for tumor relapse. Hence, by eliminating non-stem cancer cells and cancer stem cells from the patient,
permanent cure is expected. Phytochemicals have been under the intensive study to target these CSCs effectively
and permanently as they do not cause any side effects. Resveratrol (RSV) is one such compound attaining lot of
interest in recent days to target CSCs either alone or in combination. RSV has been used by several researchers to
target cancer cells in a variety of disease models, however its CSC targeting abilities are under intensive study at
present. This review is to summarize the effects of RSV under in vitro and in vivo conditions along with advantages
and disadvantages of its uses against cancer cells and cancer stem cells. From the first reports on phytochemical
applications against cancer and cancer stem cells in 1997 and 2002 respectively followed by later reports, up to
date observations and developments are enlisted from PubMed in this comprehensive review. RSV is shown to be
a potential compound having impact on altering the signal transduction pathways in cancer cells. However, the
effects are variable under in vitro and in vivo conditions, and also with its use alone or in combination with other
small molecules. Past research on RSV is emphasizing the importance of in vivo experimental models and clinical
trials with different prospective combinations, is a hope for future promising treatment regimen.
1. Introduction
Resveratrol (RSV), is 3,4’,5 –trihydroxy stilbene, a phytoalexin is
widely distributed in variety of plants including red grapes, berries,
peanuts, etc. Highest levels of RSV are found in Japanese knotweed
(Polygonum cuspidatum) and muscadine grapes (Vitis rotundifolia)(Shri-
kanta et al., 2015). Though its occurrence is widely distributed about
more than 70 plant species, its bioavailability is challenging upon its
consumption (Gambini et al., 2015). Tome-Carneiro et al. (2013) have
further shown, different levels of RSV concentrations are attributed for
differential health impacts. Szekeres et al. (2010) in their review
demonstrated that, due to the presence of three hydroxyl groups, it was
known to act as a potent anti-oxidant by interfering with intracellular
redox signaling. In many studies with different model organisms, RSV is
shown to increase healthy life span mediated by SIRT1 (NAD-dependent
deacetylase sirtuin-1) (Bhullar and Hubbard, 2015). RSV can reduce in-
flammatory stress through its effects on mitochondria. It activates a
group of mitochondrial proteins of sirtuin family, particularly SIRT1.
Lagouge et al. (2006) had shown that activation of sirtuin family protein
can in turn related to the blood sugar stabilization in the body.
RSV effects on nitric oxide cycle were well known, through which it
maintains the health of immune, nervous and vascular system. Nitric
oxide in the body is synthesized by the enzyme Nitric Oxide Synthase
(NOS) which has a critical role in inflammation. NOS can occur in
* Corresponding author.
E-mail addresses: vasanthkbhaskara@gmail.com (V.K. Bhaskara), genomicsbioinformatics2976@gmail.com (B. Mittal), vijayamysorekar1@gmail.com
(V.V. Mysorekar), dr.nagarathnaa@gmail.com (N. Amaresh), jsimal@uvigo.es (J. Simal-Gandara).
Contents lists available at ScienceDirect
Current Research in Food Science
journal homepage: www.editorialmanager.com/crfs/
https://doi.org/10.1016/j.crfs.2020.10.004
Received 15 August 2020; Received in revised form 28 October 2020; Accepted 29 October 2020
2665-9271/©2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Current Research in Food Science 3 (2020) 284–295

different isoforms based on its location such as endothelial NOS (eNOS),
neuronal NOS (nNOS) and inducible NOS (iNOS). All the NOS isoforms
(eNOS, nNOS and iNOS) have been reported to be expressed in the car-
diac and endothelial cells of the blood vasculature. RSV has been proved
to show its effects by acting on eNOS derived NO system thus inhibiting
the damage caused due to stress-induced inflammation (Xia et al., 2014).
These effects are well established functions of RSV on cardiac health.
However, RSV has also been shown to exhibit broad-spectrum antimi-
crobial, anti-infective, anti-amyloidogenic activities and now researchers
are testing for the efficacy of its anti-cancer stem cell properties.
This review is a comprehensive collection of original work and re-
views to elucidate the present idea about advantage of resveratrol
application particularly against CSCs. This review is also to discuss about
in vitro and in vivo observations of RSV effects emphasizing its efficacy to
use in future cancer therapy.
2. Resveratrol mechanisms affecting cancer cells
In the recent past, a lot of interest has been aroused in revealing the
exact mechanisms of anti-cancer effects of RSV. It is a polyphenolic
stilbene with an aromatic benzene bonded to three hydroxyl groups
that acts as a potent anti-oxidant neutralizing the toxic effects of
reactive oxygen species (ROS) in the body, thereby neoplastic trans-
formation of cells can be prevented. However, the anti-cancer effects
have been reported due to other mechanism of action as its anti-oxidant
potential is not very high when compared with other biological mole-
cules. RSV has been reported to exert its anti-cancer activity by
inducing cell cycle arrest, apoptosis, differentiation and inhibiting
cancer cell proliferation. Jang et al. (1997) for the first time evidenced
that from topical application of RSV in an experimental skin cancer
mouse model tumorigenesis found to be inhibited. RSV is shown to be
effective by acting at initiation, progression and metastasis stages of
tumorigenesis (Ko et al., 2017).
There are myriad pathways that RSV has been shown to influence on
cancer cells. However, these effects are observed to be limited by the
experimental conditions. Still it requires significant efforts to identify
cross-talk pathway effects and to select the common key targets in cancer
cells. Figs. 1–2.
2.1. Resveratrol structure and anti-cancerous activity relevance
Resveratrol is 5-[(E)-2-(4-hydroxyphenyl)ethyl]benzene-1,3-diol
with three hydroxyl groups attached to carbon atom of the two aro-
matic ring structures. In plants it is synthesized to provide protection
against the environmental stress and to a variety of infections. The
therapeutic effects of resveratrol originally started from the concept of
“French paradox”, which came into an existence in the year 1992 in an
epidemiological study by Renaud and de Lorgeril (1992), to understand
the effect of wine consumption on coronary heart disease (CHD). Later
studies have characterized different compounds in red wine with a va-
riety of flavanols like myricetin, kaempferol, quercetin (predominant),
catechin, epicatechin, oligo- and poly-meric flavan-3-ols, proanthocya-
nins, anthocyanins, phenolic acids such as gallic acid, caftaric acid, caf-
feic acid, p-coumaric acid and the resveratrol (stilbene).
The compounds with polyphenolic substituents particularly catechols
or 1,4 dihydroquinone are unique in forming stable phenoxyl radical
upon reaction with oxidizing agents like superoxide radicals, peroxyni-
trite, etc., formed in the cells posed under oxidative stress. As wine was
found to be enriched with catechols, its effects initially were explained
for anti-fungal, potential anti-platelet aggregation and anti-oxidant
Acronyms list
ABC ATP-binding cassette transporters
ALDH Aldehyde dehydrogenase
AML Acute myeloid leukemia cells
AT/RT Atypical teratoid/rhabdoid tumor
Bax Bcl2 associated X protein
Bcl2 B-cell lymphoma-2
BNIP3 BCL2/adenovirus E1B 19 kDa protein-interacting protein-3
CD Cluster of differentiation
CDK Cyclin-dependent kinase
CHD Coronary heart disease
COX Cyclooxygenase
CSCs Cancer stem cells
CYP Cytochrome P450
DAPK2 Death associated protein kinase-2
EMT Epithelial to mesenchymal transition
eNOS Endothelial nitric oxide synthase
ER Estrogen receptor
ERK Extracellular signal regulated kinase
ESA Excretory secretory antigen
FA Fanconi anemia
FAS Fatty acid synthase
GBM Glioblastoma multiforme
HER-2 Human epidermal receptor-2
HIF-1
α
Hypoxia inducible factor -1
α
IL Interleukins
iNOS Inducible nitric oxide synthase
JAK Janus kinase
lncRNA Long non-coding RNA
ALT-1 Mucosa-associated lymphoid tissue lymphoma
translocation protein
MAP Mitogen activated protein kinase
MCP-1 Monocyte chemoattractant protein-1
MDR1 Multi-drug resistance protein-1
MEK Mitogen activated protein kinase - MAPK Kinase
MMP Matrix metallo proteinase
MRP1 Multidrug resistance associated protein-1
mTOR Mammalian target of rapamycin
NAC N-acetyl cysteine
NF-κB Nuclear factor kappa B
nNOS Neuronal nitric oxide synthase
NO Nitric oxide
Nrf-2 Nuclear factor erythroid-2 related factor-2
ODD Ornithine decarboxylase
PI3K Phosphoinositide 3-kinase
PPAR Peroxisome proliferator-activated receptor
QR2 Quinone reductase-2
RAF Rapidly accelerated fibrosarcoma protein kinase
RAS Rat sarcoma protein kinase
RCC Renal cell carcinoma
ROS Reactive oxygen species
RSV Resveratrol
SCC Squamous carcinoma cell
SERM Selective estrogen receptor modulator
SIRT1 NAD-dependent deacetylase sirtuin-1
SREBP1 Sterol regulatory element binding protein-1
STAT Signal transducer and activator of transcription
TGF Transforming growth factor
TNBC Triple negative breast cancer
TRAIL Tumor necrosis factor related apoptosis inducing ligand
TrxR Thioredoxin reductase
VEGF Vascular endothelial growth factor
V.K. Bhaskara et al. Current Research in Food Science 3 (2020) 284–295
285

properties (Waterhouse, 2002). RSV accumulation in grape plants was
found to be formed in response to Botrytis cinerea and other fungal in-
fections. In the plants, oligomers of RSV are known as viniferins that are
actual anti-fungal compounds. In wine, cis-,trans- and glucosides of both
cis- and trans-resveratrol are found. Trela and Waterhouse (1996) have
observed that in plants, cis-resveratrol is absent and is formed in wine due
to light induced cis/trans isomerization. In dietary products, RSV occurs
in glycosylated form known as “piceid”which is resistant to undergo
enzyme mediated oxidation, thereby retaining its biological effects.
However, intestinal cells absorb free form of RSV after the action of
glycosidases there by enzyme activity is related to the absorption of RSV
into the body (Fan et al., 2009).
Resveratrol in wine was explained as an important derivative of red
grapes and as a constituent of biological fluid that could prevent tumor
growth for the first time in 1997. Due to its structural similarity with that
of the diethylstilbestrol which is a synthetic estrogen, RSV was consid-
ered as a phytoestrogen. RSV was found to inhibit the binding of radio-
labeled estradiol to estrogen receptor responsible for variable effects
under different test systems relating its influence on breast cancer (Gehm
et al., 1997). It was reported that RSV has 16 times lower anti-oxidant
potential than the
α
-tocopherol. But unlike other polyphenol mole-
cules, RSV can undergo redox cycling being able to adopt quinone like
structure. ROS production in the cell reported to cause activation of
nuclear factor erythroid-2 related factor-2 (Nrf-2) which regulates the
oxidative stress. Further, it was shown to improve recycling and
cross-talk interactions with central and lipid metabolism along with
modulating phase-I and II metabolism enzymes and transporters.
Quinone reductase-2 (QR2), a phase-II detoxifying enzyme shown to
interact directly with RSV. Inhibition of QR2 by RSV can induce other
cellular anti-oxidant enzymes and thus increases cellular resistance to
oxidative stress (Britton et al., 2015).
It has been shown that several methylated compounds generate
formaldehyde in the cell, which was shown to be effectively being pre-
vented by RSV. Further, the reaction products formed during the inter-
action between RSV and formaldehyde can act as chemopreventive
factors (Tyihak et al., 1998). Thus Szende et al. (1998) reported that RSV,
due to its formaldehyde capturing ability can influence cell proliferation
and active cell death in a dose-dependent manner. Further, Fontecave
et al. (1998) also shown that RSV can act as a potent inhibitor of ribo-
nucleotide reductase and DNA synthesis in mammalian cells thereby
controlling the cell proliferation and exhibiting chemopreventive activity.
After ingestion, RSV undergoes a variety of biotransformation in the
intestinal cells, liver cells and then by the gut microbiome. From the diet,
about 75% of RSV gets assimilated and metabolized rapidly and exten-
sively to form conjugated products. Remaining 25% of ingested RSV will
be excreted directly through urine. About 2% of RSV in plasma can be
regenerated from the conjugated metabolites upon hydrolysis by the
enzymes of microbiome. Though some biological effects have been
shown to exert by RSV metabolites, in the literature the anti-cancer ef-
fects are mainly attributed only for the free form of RSV (Springer and
Moco, 2019).
2.2. Anti-proliferative effects
Cancer cell proliferation is attributed due to an aberrant Mitogen
Activated Protein (MAP) kinase signaling pathways. Constitutive
activation of RAS/RAF/MEK/ERK (extra-cellular signal regulated ki-
nase) pathway has significant role in the sustained cancer cell survival
and proliferation. In different cancers, alterations mostly may occur at
the receptor level or due to consecutively mutated downstream kinases
of the respective pathways. For instance, in pancreatic cancers,
epidermal growth factor (EGF) and/or human epidermal receptor-2
(HER-2) mutations are critically responsible for cancer cell prolifera-
tion (Oliverira-Cunha et al., 2011). Further, cancer cells secrete
vascular endothelial growth factors (VEGF) that can induce neo-
vascularization and that may in turn provoke cell proliferation. In
renal cell carcinoma cells (RCCs) including ACHN and A498, RSV
treatment is found to exert its effect on RCC proliferation, migration
and invasion in a concentration dependent manner through inactiva-
tion of the Akt and ERK1/2 signaling pathways (Zhao et al., 2018).
RSV is observed to have effect on VEGF expression mediated regula-
tion of cell proliferation under in vitro condition (Liu et al., 2012). In
CaCo-2 cells, treatment with 25
μ
M RSV has shown 70% growth in-
hibition due to S/G2 phase arrest. These effects were shown to be due
to the inhibition of ornithine decarboxylase (ODD) activity which is
enhanced in cancer cells (Schneider et al., 2000).
2.3. Cell-cycle arrest and pro-apoptotic effects
RSV is reported to be responsible for cell cycle arrest thereby
inducing the cancer cells to undergo apoptosis. Singh et al. (2017) re-
ported that the combined drug treatment of RSV and docetaxel on
Fig. 1. Resveratrol effects on cellular pathways and its mediated anti-cancer effects.
V.K. Bhaskara et al. Current Research in Food Science 3 (2020) 284–295
286

C4–2B and DU-145 cell lines of prostate cancer was found to be
responsible for inhibited progression of G2/M phase arrest and also
enhanced expression of pro-apoptotic genes of Bax,Bid and Bak.Inan
another study, Yuan et al. (2015) reported that A549 cells of lung
cancer, upon treatment with RSV was found to arrest the cell cycle in
G
0
/G
1
phase by down regulating the expression levels of cyclin D1,
cyclin-dependent kinase-4 (CDK4) and CDK6 along with an upregulated
expression of CDK inhibitors, p21 and p27 in a p53 independent
manner. Mitochondria in the cell have a very critical role in normal cells
to decide cell survival and death fates through maintenance of an
optimal Bcl2/Bax ratio. Kumar et al. (2017) shown that RSV treatment
has resulted in decreased cell viability, altered cell morphology and
increased apoptosis in a dose, time and caspase-independent manners in
murine prostate cancer. These effects were due to the influence of the
RSV via disrupted mitochondrial membrane potential and aberrant
expression of Bax/Bcl-2 proteins.
2.4. Anti-metastatic effects
Metastasis is the later event of tumor progression that causes seeding
of tumor cells in distant metastatic sites ultimately leading to the for-
mation of secondary tumors. De-differentiation of cancer cells in later
stages that gets induced by tumor microenvironment has been reported
to be associated with enhanced metastatic abilities of cancer cells due to
acquired stemness (Quail and Joyce, 2013). Cancer stemness is known to
enhance the metastatic potential of several cancer types leading to
aggressive secondary tumor formation at different sites (Lif et al., 2007;
Li and Li, 2014). Ji et al. (2013) reported in an in vitro study, RSV
Fig. 2. Resveratrol isomers &its immediate metabolites.
V.K. Bhaskara et al. Current Research in Food Science 3 (2020) 284–295
287

treatment lead to inhibited invasion and metastasis of colorectal
cancer-derived cell lines LoVo and HCT116 by suppressing the
Wnt/β-catenin signaling mediated target genes of c-Myc, MMP-7, and
MALT-1. At low doses, RSV is shown to be effective against breast cancer
metastasis to lungs in mice by its inhibitory effect on Stat3 mediated
signaling (Lee-Chang et al., 2013). The metastasis of 4T1 mouse breast
cancer cells both under in vitro and in vivo conditions upon RSV
pre-treatment was found to inhibit cancer cell metastasis through its
inhibitory effect on MMP-9 expression (Lee et al., 2012).
3. Strategies to eliminate cancer stem cells
Most of the tumor tissues types were first discovered to contain het-
erogeneous cell population with distinct levels of therapeutic resistance,
self-renewal capacities, low-proliferation rate and with the ability to
repopulate original tumor cells (Chang, 2016). Further, these populations
of cells were named as cancer stem cells, which are responsible for chemo
resistance and tumor relapse (Nguyen et al., 2012). It has been concluded
from different reports, that by eliminating cancer stem cells completely
from the tumor site, permanent cure for cancer can be achieved. Hence,
targeting the minor cancer stem cell population is a very important and
prospective strategy of cancer treatment.
There have been different strategies in the literature to eliminate
these CSCs such as inducing CSC differentiation and then targeting by
potent apoptotic inducers, by targeting DNA damage repair enzymes,
by targeting cell cycle specific regulators, by using monoclonal anti-
bodies, by altering the drug resistance genes and recently by meta-
bolism based therapeutic targeting. These strategies are dependent on
the cancer type, specific to the stage and based on experimental system
under the study (Yoshida and Saya, 2016;Jagust et al., 2019;Shibata
and Hoque, 2019). RSV is reported to regulate all the major CSC
signaling pathways, but exact mechanisms of its interactions are not
clearly understood (Zhang et al., 2018). In spite of the promising
results of CSC targeting under in vitro conditions, it require robust
research to translate the observations to in vivo systems and further to
the clinical settings.
3.1. Therapeutic resistance of cancer stem cells and resveratrol
Cancer stem cells are described to exhibit endogenous resistance
mechanisms against radiation and chemotherapy due to preferential
activation of DNA damage response, hypoxic stability, an increased ac-
tivity of ABC transporters leading to efficient drug efflux, elevated
expression of anti-apoptotic molecules, higher aldehyde dehydrogenase
(ALDH) activity/enhanced activity of repair enzymes and quiescence or
dormancy or Go –Phase (Prieto-Vila et al., 2017;Cho and Kim, 2020).
Resveratrol has been shown to reverse the resistance to standard classical
chemotherapeutics in non-stem cancer and cancer stem cells by sensi-
tizing the cells in multiple ways. It is reported to cause an increased
susceptibility to induce cancer cell apoptosis by interfering with pro- and
anti-apoptotic factors, by regulating miRNAs, by its effect on drug- and
carcinogen-metabolizing enzymes, by interfering with drug resistance
gene/protein expressions and respective signaling pathways through
poorly understood mechanisms (Mieszala et al., 2018;Zhang et al.,
2019).
Kao et al., (2009) and Lu et al., (2009) have reported that effects of
radiotherapy in RSV pretreated medulloblastoma (MB) cancer stem-like
cell cultures and CD133 –positive cells derived from atypical ter-
atoid/rhabdoid tumor (AT/RT) was reported to be significantly
enhanced. Radiation combined with RSV pretreatment was observed to
significantly increase the radiosensitivity in MB-CSCs. Similarly,
AT/RT-CD133 (þ) cells with CSC properties when treated with RSV,
reported to inhibit expression of drug resistant genes and induced dif-
ferentiation of AT/RT CD133(þ) cells to drug-sensitive CD133() cells.
RSV was reported to induce chemosensitization to 5-fluorouracil through
inhibition of epithelial-mesenchymal transition (EMT) factors and down
regulation of NF-κB regulated (inhibited IκB
α
kinase and IκB
α
phos-
phorylation and degradation) gene products like MMP-9, caspase-3 in
colorectal cancer cells (Buhrmann et al., 2015). Choi et al. (2016) re-
ported that RSV analog HS-1793, found to enhance radiosensitivity in
mouse-derived breast cancer cells under hypoxic conditions through
inhibiting the hypoxia-inducible factor-1
α
(HIF-1
α
) and VEGF protein in
FM3A mouse mammary carcinoma cells. Tumor necrosis factor related
apoptosis-inducing ligand (TRAIL) armed oncolytic adenovirus known as
ZD55-TRAIL, reported to enhance A549 sphere cell apoptosis through
mitochondrial pathway up on treatment of RSV along with small mole-
cules embelin and LY294002 and thus shown an improved survival status
of lung cancer mouse models (Yang et al., 2015a,b,c). Zhou et al. (2019)
reported an increased chemotherapeutic response by RSV pretreatment
which has reversed the stemness induced by gemcitabine in pancreatic
cancer cells of MiaPaCa-2 and Panc-1 cells via targeting sterol regulatory
element binding protein-1 (SREBP1). In SKOV3 - cancer stem cells of
ovarian cancer, RSV found to potentially increase the tumoricidal effect
of chemotherapeutic doxorubicin under in vitro conditions (Pouyafar
et al., 2019a,b). Though couple of studies indicated role of RSV in
reversing the cancer stem cell drug resistance, its mechanism of inter-
vention has to be understood in detail in in vivo models and in human
trials.
3.2. Natural products strategy
Recently, there has been a lot of attention on natural dietary product
characterization with medicinal properties that can control cancer cells
preventing their progression. Further, these compounds have attained
importance in research and drug discovery due to their less or no toxic
side effects (Rajesh et al., 2015). Panche et al. (2016) had discussed in
detail about the current trends of research and developments on flavo-
noids as potential drug candidates. Different chemical ingredients in the
diet consumed in day-to-day life have been studied for their potential
benefits. Newman and Cragg (2016) have reported that from the year
1981–2006, nearly 63% of anticancer drugs used have been developed
from natural products. Applications of these natural products are shown
to be particularly important in cancer therapy as they do not pose any
side effects.
3.3. Resveratrol strategy
RSV is one of the natural products, which was known to be respon-
sible for cardiac health and now the same RSV has generated a lot of
interest for its anti-cancerous effects. Jang et al. (1997) reported for the
first time that the RSV's anticancer effect was due to its anti-initiation,
anti-promotion and anti-progression activities.
RSV was reported to exhibit selective estrogen receptor modulator
(SERM) activity and this observation further laid possibility of its role in
breast cancers (Gehm et al., 1997). Gunther et al. (2007) found that RSV
can also be used to target CSCs by observing in an attempt to test the
polyphenols including RSV that could prevent the cell shedding from
mouse mammary cancer spheroids inhibiting the cancer cell invasion of
embryonic stem cell cultures. However, Wallenborg et al. (2009) re-
ported that by using small amount of red wine (1–5%) containing RSV
exhibited massive cell death of various cell types including neural stem
cells had taken place due to increased oxidative stress mediated inhibi-
tion of thioredoxin reductase (TrxR) activity but not due to RSV.
Resveratrol was shown to exert effect by the down regulation of fatty acid
synthase (FAS) gene and up-regulation of pro-apoptotic genes like DAPK2
and BNIP3 in cancer stem –like cells (CD24()/CD44(þ)/ESA(þ) which
were isolated from both ERþand ER-breast cancer cell lines. These al-
terations were observed to cause inhibited cell viability and mammo-
sphere formation along with induced pro-apoptotic effects (Pandey et al.,
2011). There are total 160 results have been displayed which are relevant
to resveratrol and cancer stem cells in the PubMed search. It is also
interesting to note that, from the year 2015 there has been increasing
V.K. Bhaskara et al. Current Research in Food Science 3 (2020) 284–295
288

Table 1
Summary of historical review of RSV effects in various CSC model systems reported.
Ref. CSC model system RSV Effects
Gunther et al. (2007) 4T1 Mouse mammary breast cancer cells. Cell shedding from mouse mammary cancer spheroids ↓
Cancer cell invasion in embryonic stem cell cultures ↓
Kao et al. (2009) CD133-positive/negative cells derived from atypical teratoid/
rhabdoid tumors (AT/RT-CD133()).
With 200
μ
Mtreatment; in vitro proliferation and in vivo tumor relapse of
CD133(þ) cells ↓
With 150
μ
M treatment;
Drug resistance genes in CD133(þ) cells ↓
Differentiation of CD133(þ) cells into CD133()↑
Lu et al. (2009) Medulloblastoma (MB)-associated 3D-spheroid forming CSCs Proliferation and Tumorigenicity of MB-CSCs ↓
Radiosensitivity ↑
Shankar et al. (2011) Human pancreatic Cancer Stem Cells (CD133þ, CD44
þ
, CD24
þ
,
ESAþ) of NOD/SCID mice, CSCs from Kras
G12D
transgenic mice and
human pancreatic tumor derived CSCs.
Caspase 3/7 ↑Expression of XIAP, BCL-2 and CCND1 ↓
Pandey et al. (2011) CD24()/CD44(þ)/ESA(þ) cells from estrogen receptor –ER
þ
and
ER

breast cancer cell lines.
Lipogenesis by modulating FAS expression ↓
Apoptosis ↑
Hu et al. (2012a,b) Human promyelocytic leukemia stem cells (KG-1a) KG-1a cells susceptible to cytokine-induced killer cell (CIK) mediated cytolysis
↑
Hu et al. (2012a,b) CD44 positive head and neck cancer (HNC) cells; HNC-Tumor
Initiating Cells (TNCs)
Trans-differentiation of head and neck cancer-derived tumor-initiating cells
(HNC-TICs) ↑EMT ↓
Hagiwara et al. (2012) Orthotopic inoculation of female SCID mice with MDA-MB-231-luc-
D3H2LN cells in pretreated mice with resveratrol.
Tumor suppressive miR-141 and miR-200c expression ↑
CSC phenotype ↓
Sato et al. (2013) Patient-derived Glioma Stem Cell (GSCs) cultures and Intracranial
xenograft models of GSCs
p53-Nanog axis mediated Differentiation of GSCs ↑
Su et al. (2013) Human AML HL-60 cell lines and patient derived samples Sonic hedgehog (Shh) ↓
Gli-1 nuclear translocation ↓
Cell viability ↓
IL-6 treatment induced the growth of AML cells through Shh signaling which
was blocked by RSV treatment.
Sayd et al. (2014) Glioblastoma Stem Cells (GSCs): Derived from Human glioblastoma
tissue
Normal Neural Stem Cells (NSCs): Derived from human fetal brain
tissue
GSC proliferation ↓up to 150
μ
M and necrosis ↑at higher doses.
However, it has no effect on NSCs.
These effects on GSCs are mediated through Sirtuin-2 which has vital
enzymatic function in tumor metabolism.
Fu et al. (2014) Breast cancer stem-like cells (BCSCs) isolated from MCF-7 and
SUM159
Administration of 100 mg/kg/day in NOD/SCID mice resulted xenograft
tumors size ↓
BCSC cell population in tumors ↓
Autophagy in BCSCs ↑
Yang et al. (2015a,b,c) Colorectal cancer stem cells In vitro Administration of 12.5–200
μ
mol/L resulted in HCT116 CCSC proliferation ↓
in a dose-dependent manner.
Seino et al. (2015) Ovarian cancer stem cells In vitro ↑Apoptosis of ovarian cancer stem cell A2780 independent of ROS
↓Self-renewal capacity of A2780 stem cells depending on ROS
Clark et al. (2017) Multiple patient-derived GBM stem-like cell (GSC) lines and
established U87 glioma cells.
GBM and GSC growth and infiltration ↓through modulation of AKT and p53
Cilibrasi et al. (2017) Human glioblastoma tissue derived glioma stem cells (GSCs) from
different patients.
Cell proliferation ↓
Cell mortality ↑
↓Cell motility through modulated Wnt signaling and EMT pathway
mediators.
Ruiz et al. (2018) Enriched CSCs derived from cervical cancer HeLa cell lines RAD51 expression ↓
CD49f-positive stem cell apoptosis ↑
Fei et al. (2018) Malignantly transformed dendritic cell line SU3-ihDCTC induced by
glioma stem cells.
In vitro co-cultured GSC induced malignant transformed bone marrow derived
dendritic cells exhibited increased sensitivity to chemotherapeutics after RSV
treatment.
Peng and Jiang (2018) Human osteosarcoma cell lines –MNNG/HOS, MG-63 and Osteoblast
line hFOB1.19.
JAK2/STAT3 ↓
Osteosarcoma cell proliferation ↓Tumorigenesis ↓
Song et al. (2019) LN18 and U87glioblastoma cells; U87 xenograft models Epithelial to mesenchymal transition (EMT) of glioblastoma cell lines LN18,
U87 and U87 xenografted mice models ↓
Expression of β-catenin ↓
GBM Stem cell marker expression:
Twist ↓
Snail↓
Slug ↓
MMP-2 ↓
MMP-9 ↓
Smad ↓
Buhrmann et al. (2019) HCT116, RKO, SW480 colorectal cancer cell monolayer and 3D
alginate cultures.
TNF-β/TNF-βR↓
Epithelial-to-mesenchymal transition ↓through NF-κB↓and focal adhesion
kinase (FAK) ↓
Segun et al. (2019) Breast (MCF7), liver (HepG2), lung (A549) and prostrate (PC3)
carcinoma cell lines versus normal prostrate epithelial cell (PNT2)
cell lines
Four RSV derivatives: (E)-resveratrol 3-O-rutinoside (1), 5-methoxy-(E)-
resveratrol 3-O-rutinoside (2), pinostilbene (3) and 3-hydroxy-5-methoxy-
benzoic acid (4) isolated from the stem bark extract of C africana tested for
anti-cancer stem cell activities.
Except the derivative –4, all the remaining derivatives were observed to be
cytotoxic across the four cell lines.
Jhaveri et al. (2019) U-87 MG: an astrocytoma grade IV cell line and LN-18: a grade IV
glioblastoma cell line neurosphere cultures
Transferrin targeted liposomal formulations of Resveratrol (Tf-RES-L) used to
treat GBM neurospheres.
Both free RSV and RSV-formulations were found to Anchorage-independent
growth of GBM neurospheres ↓
Its action exhibited through transferrin and ↑activated caspase –3/7.
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number of reports in the same field of research. Though majority of the
attempts made were with in vitro model systems, many experiments were
also reported by using in vivo models. Differential effects of RSV observed
in various in vitro and in vivo cancer stem cell models have been presented
in Table –1.
3.4. Resveratrol impact on cancer stem cell signaling pathways
Cancer stemness is a spontaneous process and is mainly associated
with tumor micro environmental factors that modulate the signal trans-
duction pathways responsible for cancer stemness. The hallmark features
during different types of solid tumor progression includes unregulated
cell proliferation, neovascularization, hypoxia and/or intermittent hyp-
oxia, cancer stemness and metastasis. Thus cancer stemness is presum-
ably known to appear at the terminal stage during the tumor progression.
However, there are no evidences to prove association of CSCs during the
initial stages. This is another interesting area to check the stage specific
effects of RSV associated with cancer stemness.
Major functional signaling pathways attributed for cancer stemness
that are experimentally evidenced and are used for therapeutic targeting
includes Wnt, nuclear factor-κB (NF-κB), Notch, hedgehog, janus kinase/
signal transducer and activator of transcription (JAK-STAT), PI3K/AKT/
mTOR (Phosphoinositide 3-Kinase/AKT/mammalian target of rapamy-
cin), transforming growth factor (TGF)/SMAD and peroxisome
proliferator-activated receptor (PPAR) pathways (Yang et al., 2020).
Though some of these pathways were found to have role in cancer
stemness, only anti-cancer properties of RSV were reported and its
anti-cancer stemness effects are yet to be evidenced. It has been reported
that in Indian triple negative breast cancers (TNBC) patients, the putative
cancer stem cell marker CD133 or prominin-1 is correlated with the
functional CSC signaling pathways including NOTCH-1/HES-1;
Wnt/β-catenin; TGF-βIII R/SMAD-7 and PTCH-1/Gli-1 (hedgehog)
pathway activations (Bhaskara et al., 2019).
Phytochemicals can act as small molecular receptor blockers, kinase
inhibitors, protease inhibitors, pro-apoptotic factors, spindle poisons,
DNA damaging agents and cell cycle inhibitors that can influence the
modulation of signaling pathways in order to impede or cure cancer. RSV
effects on NOTCH signaling pathways are unique in a way that, it causes
activation rather than inhibition of different proteins of NOTCH signaling
leading to its anti-cancer activity (Farooqi et al., 2018). RSV has been
shown to be affecting diverse cancer stemness signaling pathways that
control not only the cancer stemness but also other cancer properties like
cell viability, proliferation, apoptosis induction, inhibiting cell migra-
tion, etc. as reported by different researchers in various model systems
enlisted in Table –2.
3.5. Resveratrol effects in combination with other molecules
The cell environment is a multi-factorial system and biologically
active phytochemicals in its isolation shows differential effects due to the
possible lack of secondary metabolite interaction with other molecules.
Further, drug targeting by multiple strategies is one of the effective
treatment regimens in cancer therapy and management, to come over the
multi-drug resistance (MDR). Based on these facts, RSV treatment strat-
egy was used in combination chemoprevention with other natural active
molecules or small molecular drugs by several researchers to find the
improved efficacy of RSV action. Pace-Asciak et al. (1995) reported that
trans-resveratrol and quercetin combination present in red wine has
shown to exhibit dose-dependent inhibition of both thrombin-induced
and ADP-induced platelet aggregation preventing atherosclerosis more
effectively. Initially RSV was found to be a potent anti-oxidant molecule
that can prevent carcinogenesis, later several reports have indicated that
it can mediate its actions through multiple ways by interacting with
several molecules. Quercetin is another phytoconstituent that has been
widely distributed in vegetables and fruits with many health enhancing
effects along with anti-cancer effects like loss of cancer cell viability,
inducing apoptosis and autophagy through PI3K, Wnt and MAPK
pathway modulation (Anand David et al., 2016;Reyes-Farias and
Carrasco-Pozo, 2019). Nam et al. (2016) have mentioned the various
methods for nanofabrication of quercetin formulations and its applica-
tions in oncotherapy. The first combination of RSV tested was with
quercetin on oral cancer cell growth and proliferation. It was reported
that by treating with 50
μ
M RSV along with 10, 25 and 50
μ
M of quer-
cetin which is another natural active component in common foods, oral
squamous carcinoma cell (SCC-25) resulted in gradual significant in-
crease in the inhibitory effect of quercetin on cell growth and DNA
synthesis. Effective inhibition of SCC-25 cell growth and proliferation
was reported due to enhanced activity of quercetin in presence of RSV
(ElAttar and Virji, 1999). Combinational chemoprevention is only
possible strategy to manage cancer cells and the same could be tested to
target cancer stem cells. Different reports using various cancer and CSC
models treated with RSV in combinations and their effects are presented
in Table 3.
3.6. Limitations of resveratrol in therapy
The critical point of limitation found in RSV literature is lack of suf-
ficient in vivo and human trial based evidences. Its observations are
mainly limited due to its bioavailability under in vivo system and also due
to differential effects with different RSV concentrations. Further, there is
a need for clear understanding for the roles of RSV metabolites along
with free form of RSV as chemotherapeutic in cancer patients. Zykova
et al. (2008) reported that in human colon adenocarcinoma HT-29 cells
shown inhibited Cox-1 and Cox-2 by both RSV and its metabolite
RSV-40-O-sulfate. In another study, the hydroxylated metabolites of RSV
formed from gut microbiota have exerted cytotoxic properties (Bode
et al., 2013). These effects in other type of cancers and in clinical studies
require proper validation.
It was established for RSV effects like NF-κB activity regulation,
inhibiting cytochrome P450 isoenzyme (CYP A1), cyclooxygenase (COX)
activity, TP53, FAS/FASL or CD95 induced apoptosis, inhibiting the HIF-
1
α
and VEGF expression through which its anti-cancer properties are
sought. There are few clinical trials with RSV as oral administration or
micronized formulations for different type of cancer patients. Few studies
have indicated its advantageous effect by modulating the targeted mol-
ecules, few were inconclusive and other few studies have resulted with
Table 1 (continued )
Ref. CSC model system RSV Effects
Zhou et al. (2019) MiaPaCa-2 pancreatic cancer cell lines and KPC mouse models of
pancreatic ductal adenocarcinoma (PDA)
Pretreatment reversed the stemness induced by gemcitabine by targeting
sterol regulatory element binding protein - 1 (SREBP1) both in vitro and in vivo .
Yin et al. (2020) Patient tissue derived ‘gastric-cancer-derived-mesenchymal stem
cells –GC-MSCs
IL-6, IL-8, MCP-1,VEGF expression ↓
β-catenin nuclear translocation in GC-MSCs upon pretreatment with RSV ↓
Metastasis of GC-MSCs ↓
Sun et al.(2020) ACHN and 786-O derived renal carcinoma stem cells Size and number of tumor spheres ↓
Sonic hedgehog (Shh) pathway related proteins: SHH, SMO, Gli1, Gli2 ↓
CSC marker proteins: CD44, CD133, ALDH1A1, Oct-4, Nanog ↓
Cell proliferation ↓
Apoptosis ↑
V.K. Bhaskara et al. Current Research in Food Science 3 (2020) 284–295
290

Table 2
Summary of RSV impact on cancer stem cell signaling pathways reported.
Signaling Pathway Experimental Model Systems RSV Effects Ref.
Notch signaling Glioblastoma cell lines (A172 and T98G) Notch-1 activation ↑dependent p53 mediated anti-
proliferative and pro-apoptotic effects
Lin et al. (2011)
Human GI carcinoid tumor cell lines (BON); Human
pulmonary carcinoid cell lines (NC–H727)
Growth ↓through S-phase cell cycle arrest
Expression of neuroendocrine (NE) peptides/hormones
chromogranin A and serotonin through activation of the
Notch-2 isoform ↑
Pinchot et al. (2011)
Anaplastic Thyroid Carcinoma (ATC) Cell Lines (HTh7 and
8505C)
Dose-dependent inhibited ATC growth ↓
Cell differentiation ↑via activation of Notch-1 signaling ↑
Yu et al. (2013)
Wnt signaling Colorectal cancer cell lines (LoVo cells) Dose-dependent inhibition of the nuclear localization of
β-catenin ↓c-Myc and MMP-7 ↓
Cell proliferation and invasion ↓
These effects of RSV are opposite to that of the long non-
coding RNA-MALAT1 cell proliferation and invasion abilities
Ji et al. (2013)
Human normal breast epithelial cell line (MCF10A) and
breast cancer cell line (MCF-7, SUM159)
Wnt/β-catenin pathway proteins ↓
β-catenin ↑markedly reduced RSV-induced cytotoxicity and
autophagy
Fu et al. (2014)
Human normal (CCD112CoN) and colorectal cancer cell
lines (HCT116, SW480, LoVo and CaCo-2)
TCF4 transcription factor expression ↓via wnt/β-catenin
pathway
Phosphorylation of TCF4 ↑via ERK and P38 dependent
pathways Apoptosis ↑
Jeong et al. (2015)
Glioblastoma patient derived stem cells (GBM2, GBM7,
G144, G179, G166, GliNS2, GBM04)
Wnt and EMT activator mediated GSC cell proliferation ↓
Cell mortality ↑
Cell motility↑
Cilibrasi et al. (2017)
Squamous cell carcinoma cell line (Colo 16 cells) RSV (100
μ
M) exhibited Wnt ↓leading to Cell growth ↓
Apoptosis ↑
Transfection with β-catenin-specific siRNA enhanced RSV
susceptibility
Liu et al. (2017)
GC-MSCs derived from the gastric adenocarcinoma patient
tissues
RSV reversed the progress of EMT Metastasis ↓
Wnt/β-catenin pathway proteins ↓
Yin et al. (2020)
SHH signaling
(Sonic Hedgehog
Pathway)
Chronic myeloid leukemia cells (K562 cells) RSV acted as Bcr-Abl inhibitor
SHH pathway proteins ↓patched (PTCH) ↓
Smoothened (Smo) ↓
Gli-1 ↓
Viability of CML cells ↓
Liao et al. (2012)
Acute Myeloid Leukemia (AML) patient derived
mononuclear cells (MNCs).
RSV blocked IL-6 stimulated growth of AML cells through
SHH signaling
Su et al. (2013)
Human colorectal cancer cell lines (HCT116 cells) Cell viability and migration ↓
Apoptosis ↑
SHH pathway proteins ↓
Du et al. (2016)
Renal cancer stem cells (ACHN and 786-O cells) Size and number of tumorspheres ↓via SHH signaling
While purmorphamine up regulated SHH pathway and
weakened the RSV effects
Sun et al. (2020)
PI3K Signaling Human colon cancer cells (HCT116 cells) Anti-proliferative effects ↑via PTEN/PI3K/Akt and Wnt/
β-catenin pathway protein regulation
Liu et al. (2014)
Glioblastoma patient derived Glioblastoma-initiating cells
(GICs)
Invasion and migration of GICs ↓via suppressing PI3K/Akt/
NF-κB and MMP-2 expression ↓
Jiao et al. (2015)
Adriamycin resistant chronic myeloid leukemia cell line
(K562/Adr)
Anti-proliferative activities of bestatin ↑P-gp expression ↓
via PI3K/Akt/mTOR signaling pathway
Wang et al. (2016)
Human colorectal cancer cell lines (HCT116 cells) Anti-cancer activity ↑
PI3K/AKT signaling ↓
BMP7 ↑
Phosphorylation of Akt1/2/3 and PTEN ↑
Zeng et al. (2017)
Human promyelocytic leukemia cells (HL-60) and ADR
(Adriamycin)-resistant cell line (HL-60/ADR)
Drug resistance ↓via PI3K/AKT/Nrf2 signaling and MRP1
expression
Li et al. (2019)
Human acute promyelocytic leukemia cell lines (NB-4 and
HL-60 cells)
PTEN expression ↑
PI3K/AKT pathway proteins ↓
Cell proliferation ↓
Apoptosis ↑
Meng et al. (2019)
Human small-cell lung cancer cell lines (H446 cells) Cell viability ↓and apoptosis ↑via PI3K/Akt/c-Myc pathway Li et al. (2020)
Human papillary thyroid cancer cell lines (KTC-1 and TPC-
1 cells); Mouse xenograft models
Anti-tumor effects ↑of rapamycin mediated by PI3K/AKT/
mTOR pathway
Bian et al. (2020)
Murine melanoma cell line (B16–F10), human melanoma
cell line (A375)
AKT/mTOR pathway proteins ↓
Autophagy ↑
Growth, viability and migration ↓
Gong et al. (2020)
TGF/SMAD Signaling Human epidermoid carcinoma cell lines (A431) and mouse
models
Ultraviolet B (UVB) induced malignant tumor progression ↓
in p53þ//SKH-1 mice through Akt mediated TGF-β2↓
Kim et al. (2011)
Colorectal cancer cell lines (LoVo cells) Epithelial to mesenchymal transition (EMT) ↓
TGF-β1/SMAD signaling pathway ↓
Ji et al. (2015)
Human breast cancer cell lines (MDA-MB-231) and
xenograft mouse model
Migration and metastasis ↓by reversing TGF-β1 induced
EMT
Sun et al. (2019)
Human glioblastoma multiforme cell lines (LN18, U87 cells) EMT ↓
EMT-generated stem cell like properties ↓via Smad-
dependent signaling regulation
Song et al. (2019)
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291

Table 2 (continued )
Signaling Pathway Experimental Model Systems RSV Effects Ref.
NF-κB Signaling Human multiple myeloma cell lines (U266), Patient derived
MM.1 or MM.1S cells
Constitutive and IL-6 induced activation of STAT3 ↓
Constitutive activation of NF-κB↓
Cell proliferation ↓
Sensitization of bortezomib and thalidomide mediated
apoptosis ↑
Bharadwaj et al. (2007)
PPAR pathway Human colon carcinoma cell lines (SW480, HCT116, Caco2
and SW620)
Apoptosis ↑
Cell proliferation ↓in combination with PPARγ
Aires et al. (2014)
Bovine arterial endothelial cells (BAECs) and PPAR
α
knockout mice
RSV exerted agonistic activity of PPAR
α
as its direct target
mediating long term effects of RSV under in vivo conditions
Takizawa et al. (2015)
JAK/STAT Pathway Medulloblastoma cell lines (UW228-2 and UW228-3 Cells) Bcl-2 expression ↑
STAT3 ↓
Survivin, cyclin D1, Cox-2 and c-Myc ↓
Growth suppression ↑
Differentiation-like changes ↑
Yu et al. (2008)
Human osteosarcoma cell lines (MNNG/HOS, MG-63 cells),
osteoblast cell line (hFOB1.19 cells)
Cell proliferation and tumorigenesis ↓correlated with
cytokines inhibition related JAK2/STAT3 signaling blockage
Peng et al. (2018)
Human ovarian cancer cell lines (SKOV3, Caov-3, OVCAR-4
and OVCAR-8 Cells)
RSV analog –pterostilbene exhibited anti-tumor activity via
anti-proliferative and pro-apoptotic mechanisms through
JAK/STAT3 pathway ↓
Wen et al. (2018)
Table 3
Summary of RSV and its combinational chemopreventive effects.
Ref. Experimental Models Systems RSV Combinations Effects
Bader &Getoff (2006) Human Breast cancer cells –MCF7 Mitomycin C (MMC) Anti-tumor free radical scavenger activity under aerobic conditions in
presence of mitomycin ↑
Reiter et al. (2007) Human Mast Cell line-1 (HMC-1) Delta-Tocopherol Combinations of 50
μ
MRSV and 50
μ
Mdelta-tocopherol resulted:
Protein Kinase B (PKB) Ser473-phosphorylation ↓
HMC-1 cell proliferation ↓
Zhang et al. (2014) Fanconi anemia (FA) murine
models
N-acetylcysteine (NAC) Neither RSV nor NAC could have significant chemopreventive effect in FA
mouse models.
Yang et al. (2015a,b,c) Human bronchial epithelial cell
line BEAS-2B, 16HBE and Human
lung cancer cell lines –A549 and
H446.
AK001796 lncRNA AK001796 in lung cancer tissues and cells pretreated with RSV resulted:
G0/G1 cell cycle arrest ↑
In vitro and In vivo colony formation ↓
Cell growth and proliferation ↓
Li et al. (2016) Patient derived glioblastoma-
initiating cells.
Temozolamide Both in vitro and in vivo resulted:
Apoptosis ↑through DNA double stranded breaks, pATM/pATR/p53 pathway
activation ↑
cell differentiation ↑
p-STAT3 activity ↓
Hardin et al. (2016) Anaplastic thyroid cancer cell
lines –FRO, Kat18, NTHY-Ori-3,
8505C, papillary thyroid
carcinoma cell line BCPAP, TPC-1
Cell line, THJ-16T and THJ-21T
Valproic acid Stem cell marker - Aldefluor expression ↓
Proliferation ↓
Invasiveness ↓
Apoptosis ↑
Thyroid differentiation markers ↑
Yuan et al. (2017) Human ovarian carcinoma cell
line –A2780 cells
Gemcitabine (GEM) along with
Silver nanoparticles-RSV (AgNPs)
Combined GEM and AgNPs exhibited potent apoptotic activity ↑
Dewangan et al. (2017) Human breast cancer cells
(HBCCs) - MCF-7, MCF-10A
Salinomycin Apoptosis ↑via reactive oxygen species (ROS) mediated mitochondrial
dysfunction. Altered nuclear morphology
PARP cleavage ↑,
Caspase activation ↑
Modulated MAPK pathway
Mukherjee et al. (2018) C57BL/6 male mice (2–4 months
old); GL261 mouse glioblastoma
cells
TriCurin: Curcumin, Epicatechin
gallate and Resveratrol (4:1:12.5)
combination
In GL261 under In vitro: p53 ↑
apoptosis ↑
In In vivo:
Repolarization of M2-like tumor (GBM) associated microglia/macrophages to
the tumoricidal M1-like phenotype and intra-GBM recruitment of activated
natural killer cells leading to apoptosis of tumor stem cells.
Pouyafar et al. (2019) SKOV3 derived ovarian cancer
stem cells In vitro
Doxorubicin (DOX) Treated with RSV and DOX at IC
50
of 55
μ
Mand 25
η
M, respectively resulted:
BAX ↑
Caspase 3 ↑
MDR1 ↓
MRP1↓
Drug resistance to doxorubicin ↓
Apoptosis ↑
Pouyafar et al. (2019) Cancer stem cells of human
adenocarcinoma cell line HT-29
Sulindac Transcription of autophagy signaling genes: (GALNT11) ↑in cancer stem cells
Trans-differentiation ↑
Decreased cell resistance ↓
Hoca et al. (2020) PANC-1 derived CD133þand
CD133- pancreatic cancer cells
Quercetin At 5,10,25,50 and 100
μ
Mconcentrations of combined treatment of CD133þcells
resulted:
ACTA-2, IL-1β, and N-Cadherin ↓
TNF-
α
and Vimentin ↑
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V.K. Bhaskara et al. Current Research in Food Science 3 (2020) 284–295
292

certain adverse effects like nausea, diarrhea, vomiting, fatigue, anemia
and mainly renal toxicity in multiple myeloma patients (Popat et al.,
2001).
There are controversial reports which need to be reconfirmed and
studied in details. RSV was reported to promote atherosclerosis in
hypercholesterolemic rabbits rather than protecting against athero-
sclerosis (Wilson et al., 1996). Further, RSV was shown to suppress
atherosclerosis in hypercholesterolemic rabbits without affecting
plasma lipid levels (Wang et al., 2005). Zhang et al. (2014) reported
that tempol and N-acetylcysteine (NAC) or RSV when tested for its
chemopreventive effects in tumor prone Fancd2(/)/Trp53()fan-
coni anemia (FA) murine models, RSV could not show effective che-
mopreventive effect as that of tempol. There are certain clinical trials
attempted to draw conclusions for RSV as an effective chemothera-
peutic is discussed in the review by Berman et al. (2017) and they re-
ported that breast cancer and multiple myeloma patients have shown
RSV as more promising molecule but limited due to adverse effects.
Other clinical trials were made on prostate cancer, colorectal cancer
and bladder cancer patients, but require further detailed understanding
of RSV effects.
4. Conclusions and perspectives
Natural bioactive compounds in edibles with pharmacological activ-
ities have no known side effects and can have better impact by interacting
with other secondary metabolites. Hence, at present potent natural
bioactive compounds and their applications are on demand. RSV is a
well-known compound and recently its effects of targeting CSCs have
become more interesting. Being a potent reducing agent it is known to
prevent carcinogenesis due to its anti-oxidant abilities, however its
ability to regulate other molecules and mechanisms to target cancer cells
and cancer stem cells are now attaining interest.
After the initial report in 2007, in which RSV was reported to stop cell
shedding, thus inhibiting metastasis of mouse cancerous mammosphe-
roid cells, following research on CSCs have tremendously taken a peak
with most of the research groups working either with RSV alone or in
combination with other molecules to test anti-cancer stem cell effects.
There has been intervention of recent methods like effect of RSV and long
noncoding RNAs (lncRNAs) in lung carcinogenesis (Yang et al., 2015a,b,
c), inhalable resveratrol-cyclodextrin complex loaded biodegradable
nanoparticles against non-small cell lung cancer (Wang et al., 2020) and
as an immunomodulatory agent (Trung and An, 2018) in immunotherapy
of treating cancer and cancer stem cells are some areas at the front end of
modern research.
The major drawback of RSV research is that, most of the attempts
include in vitro cell culture experiments that require validation of the
same effect under in vivo conditions and with primary cultures of human
cancer tissues along with clinical trials. As RSV is a natural bioactive
compound, it should be tested with different combinations as they can
affect multiple pathways unlike targeted drug molecules which make this
strategy as unique therapeutic regiment to target cancer cells and cancer
stem cells.
CRediT author statement
All authors contribute to Conceptualization, Methodology, Investi-
gation, Writing- Original draft preparation, and Writing- Reviewing and
Editing.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
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Table 3 (continued )
Ref. Experimental Models Systems RSV Combinations Effects
TNF-
α
and N-Cadherin ↓in RSV alone treated CD133þcells
Quercetin could prevent EMT to a greater extent than RSV
Shin et al. (2020) HeLa cervical cancer adherent and
stem-like cells
Pterostilbene Pterostilbene exhibited better effects than RSV including:
Cell cycle arrest at G2/M phase
ROS-mediated Caspase-dependent apoptosis ↑
MMP-2/9 expression ↓
Tumor sphere formation and migration abilities ↓
Stemness marker expression:
CD133, Oct-4, Sox2, and Nanog ↓
STAT-3 ↓
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