cancers

Review
Dietary Polyphenols: Promising Adjuvants for Colorectal
Cancer Therapies
Laura Bracci 1, *,† , Alessia Fabbri 2,† , Manuela Del Cornò 3 and Lucia Conti 3, *

1 Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299,
00161 Rome, Italy
2 Department of Cardiovascular, Endocrine-Metabolic Diseases and Aging, Istituto Superiore di Sanità,
Viale Regina Elena 299, 00161 Rome, Italy; alessia.fabbri@iss.it
3 Center for Gender-Specific Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy;
manuela.delcorno@iss.it
* Correspondence: laura.bracci@iss.it (L.B.); lucia.conti@iss.it (L.C.); Tel.: +39-06-4990-2474 (L.B.);
+39-06-4990-3599 (L.C.)
† Equal contribution.

Simple Summary: Colorectal cancer is a leading cause of death worldwide. Despite the development
of novel surgical and therapeutic strategies, 50% of patients relapse after treatment. Therapy failure,
due to low efficacy, adverse effects and drug resistance, is thus a major concern. The idea of combining
standard therapy with non-toxic bioactive natural compounds is a recent topic in cancer research and
aims to increase the efficacy of current antitumor therapies while reducing drug toxicity and adverse
effects. In recent years, several studies have explored the capacity of polyphenols, dietary bioactive
compounds enriched in fruit and vegetables, to act as adjuvants to improve colorectal cancer therapy.
In the present review, we discuss these studies, highlighting the mechanisms underlying the adjuvant



effect, and bring out the potential of this novel therapeutic approach as well as the critical issues


related to clinical application.
Citation: Bracci, L.; Fabbri, A.; Del
Cornò, M.; Conti, L. Dietary
Abstract: Colorectal cancer (CRC) is a major cancer type and a leading cause of death worldwide.
Polyphenols: Promising Adjuvants
Despite advances in therapeutic management, the current medical treatments are not sufficient to
for Colorectal Cancer Therapies.
control metastatic disease. Treatment-related adverse effects and drug resistance strongly contribute
Cancers 2021, 13, 4499. https://
doi.org/10.3390/cancers13184499
to therapy failure and tumor recurrence. Combination therapy, involving cytotoxic treatments and
non-toxic natural compounds, is arousing great interest as a promising more effective and safer
Academic Editor: Frank A. Simmen alternative. Polyphenols, a heterogeneous group of bioactive dietary compounds mainly found in
fruit and vegetables, have received great attention for their capacity to modulate various molecular
Received: 28 July 2021 pathways active in cancer cells and to affect host anticancer response. This review provides a
Accepted: 3 September 2021 summary of the most recent (i.e., since 2016) preclinical and clinical studies using polyphenols as
Published: 7 September 2021 adjuvants for CRC therapies. These studies highlight the beneficial effects of dietary polyphenols
in combination with cytotoxic drugs or irradiation on both therapy outcome and drug resistance.
Publisher’s Note: MDPI stays neutral Despite substantial preclinical evidence, data from a few pilot clinical trials are available to date
with regard to jurisdictional claims in
with promising but still inconclusive results. Larger randomized controlled studies and polyphenol
published maps and institutional affil-
formulations with improved bioavailability are needed to translate the research progress into clinical
iations.
applications and definitively prove the added value of these molecules in CRC management.

Keywords: polyphenols; colorectal cancer; anticancer drug; preclinical study; clinical study; combi-
nation therapy
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
1. Introduction
conditions of the Creative Commons
Attribution (CC BY) license (https:// Colorectal cancer (CRC) is the third most common and the second deadliest cancer in
creativecommons.org/licenses/by/ both males and females, with more than 900,000 deaths annually worldwide [1]. Developed
4.0/). countries are at the highest risk of CRC development, thus suggesting a causal relationship

Cancers 2021, 13, 4499. https://doi.org/10.3390/cancers13184499 https://www.mdpi.com/journal/cancers

Cancers 2021, 13, 4499 2 of 17

with lifestyle. Indeed, CRC is a multifactorial disease with genetic as well as environmental
etiology. Infections, chronic inflammation, obesity and eating habits are among the main
risk factors for CRC. Over the past two decades, the survival rates of patients diagnosed
with early stage CRC have significantly improved. However, more than 50% of patients are
diagnosed with metastatic disease, for whom the five-year survival rate is approximately
10% [2]. The treatment of CRC mostly relies on surgery, which is often accompanied by
pre-operative (neo-adjuvant) or post-operative (adjuvant) chemotherapy and radiotherapy.
Treatment-related, severe adverse effects and/or drug resistance strongly contribute to
therapy failure and to tumor recurrence and progression. Thus, there is an urgent need
to explore novel non-toxic compounds that can be used in combination with standard
treatments with the aim of reducing side effects, preventing resistance and improving
tumor response to the current therapeutic options. Accumulating evidence suggests that
natural bioactive compounds, including dietary polyphenols, can exert chemopreventive
as well as direct antitumor activities by regulating several molecular targets involved
in cancer cell survival, proliferation and invasion, as well as in angiogenesis [3,4] and
immunomodulation [5]. Interestingly, some natural compounds displayed additive or
synergistic activities when combined with conventional cytotoxic therapies in CRC, thus
opening the way to clinical translation [6].
In the present review, we provide a brief overview of the role of dietary polyphenols
in CRC pathogenesis and treatment and summarize recent preclinical and clinical studies
that have explored the capacity of these compounds to act as adjuvants to CRC therapies.
Finally, we discuss the relevance of these studies in filling some gaps in CRC management
and some bottlenecks that may hamper the clinical translation of results.

2. Pathogenesis and Clinical Management of Colorectal Cancer

A growing body of evidence indicates that CRC is a multi-factorial disease, with a
variety of factors playing a role in its pathogenesis. Heritable factors account for approxi-
mately 35% of CRC risk [7]. Thus, more than 60% of CRC cases are estimated to be caused
by modifiable risk factors, such as smoking, heavy alcohol consumption, obesity, unhealthy
eating habits, physical inactivity, infections and chronic inflammation [8]. Gut microbiota
alterations can also contribute to disease [9]. Chromosomal instability (CIN), microsatellite
instability (MSI) and CpG island methylation are the three main pathways involved in
colorectal carcinogenesis [10]. Although the underlying genetic alterations have been well
characterized in CRC, the interplay between cancerous or even pre-cancerous cells and
their microenvironment (i.e., immune cells, cancer-associated fibroblast, gut microbiota)
greatly contributes to tumor development and progression [10].
At the time of diagnosis, approximately 80% of CRC cases are localized, whereas 20%
have already metastasized into distant sites. Surgical resection remains the only curative
option for colon and rectal cancers at all stages. Adjuvant chemotherapy, mainly FOLFOX
(5-fluorouracil 5-FU, folinic acid and oxaliplatin OXA) or FOLFIRI (5-FU, folinic acid and
irinotecan IRI), can help to eradicate the micro-metastases potentially occurring at the
site of surgery, whereas for locally advanced tumors, neoadjuvant chemotherapy (mainly
5-FU and capecitabine) is indicated. Furthermore, chemoradiation is often required for
locally advanced rectal cancer after surgical removal [11]. While chemotherapy is relatively
effective in the early stages of the disease, the response rate in metastatic CRC (mCRC) is
only 10–15% [12]. A combination of standard chemotherapy with more specific targeted
therapies (aimed at blocking growth factor receptors or angiogenic factors) for molecularly
defined mCRC has considerably improved survival but has also generated uncertainty
about how to identify the optimal sequence and combination [13]. Recently, regorafenib (a
multiple tyrosine-kinase inhibitor) has been approved for all patients with refractory mCRC
not responding to previous treatments. Moreover, novel promising immunotherapeutic
strategies have been authorized for patients bearing microsatellite unstable mCRC charac-
terized by a high mutation burden, which, however, accounts for only a small proportion
of patients [14]. In any case, about 50% of CRC patients will develop recurrent disease due
Cancers 2021, 13, 4499 3 of 17

to primary or acquired resistance [15]. The mechanisms that contribute to drug resistance
include the mutations of drug targets, the inactivation of apoptotic pathways, enhanced
DNA damage repair and alterations in drug metabolism [16]. The major contributors to
drug resistance in CRC are cancer stem cells (CSC), a rare subpopulation of cancer cells
endowed with self-renewal properties, unlimited cell division capability and differentiation
potential [17]. The combined administration of agents with non-overlapping mechanisms
of action and/or different cell targets and/or synergistic effects may be an encouraging
strategy to increase treatment efficacy and to reduce the side effects associated with con-
ventional treatments (i.e., neutropenia, diarrhea and gastro-, neuro- and nephro-toxicity,
among others). In this respect, natural compounds endowed with antitumor effects and low
toxicity could represent promising candidates for a combination to be further investigated.

3. Dietary Polyphenols
3.1. Classification of Polyphenols and Dietary Sources
Polyphenols comprise a large and heterogeneous group of phytochemicals containing
one or more phenol rings [18]. Depending on the number of phenol rings that they
contain and the structural elements that bind these rings to each other, polyphenols are
categorized into several classes and subclasses. The main groups are flavonoids, phenolic
acids, phenolic alcohols, stilbenes and lignans (see http://phenol-explorer.eu/compounds/
classification for an update classification (accessed on 5 June 2021)).
Polyphenols come mainly from fruits, vegetables, whole grains and beverages (fruit
juice, red wine, tea and coffee) [19]. Some of them are specifically present in particular
food (flavanols in chocolate, flavanones in citrus fruit, isoflavones in soya and phlorizin in
apples), whereas others, such as quercetin, are ubiquitously found in all plant products [19].
Generally, food contains complex mixtures of polyphenols, although most of them in the
form of esters, glycosides, or polymers cannot be absorbed in the native form. Indeed, after
ingestion, polyphenols generate several metabolites that reach cells and tissues and that
are chemically, biologically and, in many instances, functionally different from the original
dietary form, rendering the identification of active compounds extremely difficult [20].
These modifications also affect polyphenol bioavailability. The term ’bioavailability’ means
the fraction of an ingested nutrient or compound that reaches the systemic circulation and
the specific sites where it can exert its biological action. It is worth noting that bioavailability
appears to differ greatly among various polyphenols. Consequently, it is more important
to know how much of a polyphenol is bioavailable than how much of a nutrient is present
in a specific food or dietary supplement. In this regard, the role of the gut microbiota in
mediating polyphenol biotransformation and bioavailability is rapidly emerging [21], as
well as the capacity of polyphenol-rich diets to enrich specific microbial species and increase
microbial diversity [22]. In conclusion, the biological activity depends especially on the
amount of polyphenols and their metabolites accumulated in target tissues, suggesting
that the physiological in vivo context in which dietary polyphenols exert their influence
is undoubtedly much more complex than that available from an in vitro system [23]. The
same compound might show strong activity in vitro but could have little biological activity
in vivo if little or none of the compound reaches the target tissues [24].

3.2. Biological Properties of Dietary Polyphenols

Accumulating evidence from epidemiological and observational studies has suggested
possible associations between polyphenol intake and the risk of certain cancer incidence
and mortality [25–27], while laboratory studies have supported the anti-inflammatory [28],
antioxidant [29,30] and immunomodulatory activities [5,28] of natural polyphenols. In
addition, evidence is emerging on the activity of dietary polyphenols as modulators of the
colonic microbial population composition and activity [31]. Indeed, polyphenols and their
derivatives are now recognized as one of the main families of natural compounds expected
to be used as dietary factors to prevent chronic diseases [32].
Cancers 2021, 13, 4499 4 of 17

Specifically, polyphenols inactivate NF-κB and modulate crucial cell signaling path-
ways involved in inflammation and cancer, such as MAPK and PI3K/Akt pathways [28].
They can suppress toll-like receptors (TLRs) and pro-inflammatory gene expression [33].
Their antioxidant activity and ability to inhibit enzymes involved in the production of
eicosanoids also contribute to their anti-inflammation properties [28]. They inhibit cer-
tain enzymes involved in reactive oxygen species (ROS) production, such as xanthine
oxidase [34–36] and NADPH oxidase (NOX) [37,38], while they upregulate other endoge-
nous antioxidant enzymes, such as superoxide dismutase (SOD), catalase and glutathione
peroxidase. Furthermore, the ability of polyphenols to reduce the release of arachidonic
acid, prostaglandins and leukotrienes is considered one of their most important anti-
inflammatory mechanisms [28]. In addition, the modulation of cytokines and chemokines
is one of many common mechanisms by which polyphenols exert their immunomodulatory
effects. Indeed, in vivo and in vitro studies demonstrate that polyphenols affect the biology
of myeloid cells, macrophages and dendritic cells, as well as T cells and NK cells [33,39],
by inhibiting multiple key regulators of the inflammatory response, such as TNF-α, IL-1β
and IL-6 [40,41].
The effects of these biologically active compounds on the immune system are asso-
ciated with extended health benefits for different chronic inflammatory diseases [42,43],
including cancer [19,25], diabetes [44], obesity and inflammation-related diseases [45,46],
neurodegenerative disorders and cardiovascular diseases [47].

3.3. Role of Polyphenols in Colorectal Cancer Prevention and Treatment

There is convincing evidence that Western dietary patterns, characterized by a high
intake of red and processed meat and a low intake of fruit and vegetables, increase CRC
risk (https://www.wcrf.org/wp-content/uploads/2021/02/Colorectal-cancer-report.pdf
(accessed on 15 June 2021)) [48]. Conversely, adherence to the Mediterranean diet (MD),
enriched in fruit, vegetables and fiber-containing foods, has been inversely correlated
with both the risk of developing CRC and CRC-related mortality [49,50]. Accumulating
epidemiological evidence indicates that MD can also improve prognosis and the quality
of life of subjects already diagnosed with CRC, thus arguing for a role of diet and its
components in both primary and tertiary CRC prevention [51].
Polyphenols are widely represented in the MD, and a higher adherence to the MD
was shown to result in a higher polyphenol intake and an increased colonic expression
of polyphenol-derived metabolites [52]. These dietary components have received great
attention in CRC research for their chemopreventive and direct anticancer activities [31].
The antitumor effects of several compounds, belonging to the main groups of polyphe-
nols, have been investigated in in vitro studies with cancer cells and in preclinical animal
models. Furthermore, some data have also been produced regarding their application as
anticancer compounds in clinical trials, although the vast majority of these studies are
still in progress [53]. Specifically, curcumin, either as a free compound or in the form of
nanoformulations, has been shown to display chemopreventive and anticancer activities
against CRC by modulating multiple signaling pathways leading to the induction of cell
cycle arrest and apoptosis and the downregulation of epidermal growth factor receptor
expression [54]. Many studies have also proved the chemopreventive role of resveratrol in
CRC [55]. This compound was reported to trigger apoptosis in tumor cells and to suppress
colorectal tumorigenesis and inflammation in murine models [55].
Among flavonoids, quercetin and genistein were shown to affect a number of molec-
ular pathways involved in colorectal tumorigenesis and tumor progression, including
cell cycle, proliferation, apoptosis and oncogene expression, and to have a therapeutic
effect in CRC preclinical models [56]. Conversely, the anthocyanin-mediated inhibition of
colon cancer formation and growth in mouse models was reported to occur mainly via the
suppression of inflammation and the regulation of angiogenesis [57].
The multifactorial nature of CRC highlights the need for multi-targeted approaches of-
fering a more effective alternative to the current therapeutic options. Evidence is emerging
Cancers 2021, 13, 4499 5 of 17

that conventional chemotherapy in CRC significantly benefits from combined treatment

with natural products such as polyphenols [58]. The promising role of polyphenols as
sensitizers of standard chemo/radiotherapies and targeted therapies, which is discussed
in detail in the following sections, paves the way for new combined strategies able to
minimize the toxicity and side effects of conventional treatments and to reduce the risk of
tumor recurrence.

4. Dietary Polyphenols as Adjuvants in Colorectal Cancer Therapy

4.1. Beneficial Effects of Polyphenols on Colorectal Cancer Treatment: Preclinical Evidence
The idea to use polyphenols in combination therapy has received great attention
in recent decades, and a wealth of preclinical studies have been performed in order to
analyze the effectiveness of combination and the mechanisms at the basis of their beneficial
activity [58]. Here, we provide an update of the most recent literature on the effects of
the most common dietary polyphenols on standard and experimental CRC treatments
(summarized in Table 1).

Table 1. Preclinical studies on the effects of dietary polyphenols in combination with standard or experimental
CRC treatments.

Combination Main Effects of the

Polyphenol In Vitro Model In Vivo Model Ref
with Combination
↓ Proliferation and
migration,
5-FU SW620 - [59]
↓ pERK signaling,
↓ L1 expression *
↓ Tumor growth,
5-FU HCT116, HT-29 HCT116 xenograft [60]
↓ autophagy
ROS generation, ER stress,
IRI LoVo, HT-29 - [61]
apoptosis, cell cycle arrest
CSC apoptosis,
IRI resistant LoVo - ↓ CSC markers, [62]
↓ chemoresistance
↓ Drug resistance,
↓ p-p65 and Bcl-2,
OXA resistant HCT116 - [63]
↓ migration,
Curcumin ↑ caspase-3
↓ Drug resistance through
OXA resistant HCT116 - [64]
effects on miR-409-3p
↓ Tumor growth,
Regorafenib HCT116 - ↓ autophagy, [65]
apoptosis
↓ Tumor growth,
CT26-implanted ↑ DNA damage signaling,
Sildenafil + 5-FU - [66]
mice metabolic and endoplasmic
reticulum stress signaling
Sildenafil + CT26-implanted
- ↓ Tumor growth [66]
anti-PD1 mice
Patient-derived Apoptosis,
GEM - [67]
HROC ↑ immune responses
Apoptosis, altered
expression of DNA
IR HT-29 HT-29 xenografts [68]
repair-related genes,
↓ Tumor growth
Cancers 2021, 13, 4499 6 of 17

Table 1. Cont.

Combination Main Effects of the

Polyphenol In Vitro Model In Vivo Model Ref
with Combination
Apoptosis,
5-FU SW480, SW620 - ↓ cell cycle, ROS production, [69]
Curcumin analogs
↓ MMP, ER expansion
↓ Tumor growth,
FOLFOX HCT116 - [70]
↓ colonospheres formation
↑ Immunogenic apoptosis,
Curcumin +
CT26-implanted ↓ tumour growth,
Resveratrol mEHT CT26 [71]
mice recruitment of T cells and
Nanoformulation
F4/80 + macrophages
↓ TNF-β-induced tumor
HCT116, resistant metastasis,
5-FU - [72]
Resveratrol HCT116 chemosensitization of CRC
cells
Modulation of apoptotic
proteins, cell cycle arrest,
DOX HCT 116, HT-29 - [73]
blocking of the efflux
activity of p-gp
Resveratrol CT26-implanted ↓ Tumor growth,
OXA SW480 [74]
nanoformulation mice ↓ immunosuppression
↓ Cell proliferation,
apoptosis,
↓ Notch-1 signaling,
Quercetin IR HT-29, DLD-1 - [75]
↓ CSC markers,
↓ toxicity toward normal
cells
Quercetin-loaded CT26-implanted ↓ Tumor growth,
DOX - [76]
micelles mice ↓ cardiotoxicity
Multi-drug resistance
reversal,
5-FU, OXA, VCR HCT-8/Fu - ↓ cell proliferation, [77]
BPIS apoptosis, accumulation of
rhodamine-123
↓ Cell proliferation,
OXA resistant HCT116, - modeling ganglioside GM3 [78]
catabolism
↓ Drug resistance,
OXA HCT-8/Fu [79]
↓ miR-149 methylation
5-FU resistant LS174-R - Apoptosis, cell cycle arrest [80]
Kaempferol
↓ Cell proliferation and
5-FU HCT-8, HCT116 - viability, [81]
apoptosis
LoVo, HCT15,
SW48, SW48-CR, ↓ Cell proliferation,
Sylibin Regorafenib GEO, GEO-CR, apoptosis, [82]
SW620, SW480, ROS generation
HCT116 LIM1215
Chrysin,
↓ Number of tumor lesions,
Galangin and AOM/DSS-treated
5-FU - ↓ β-catenin, iNOS, and [83]
Pinocembrin from mice
Cox-2 protein expression
Propolis
Cancers 2021, 13, 4499 7 of 17

Table 1. Cont.

Combination Main Effects of the

Polyphenol In Vitro Model In Vivo Model Ref
with Combination
Apoptosis,
ROS generation,
Tangeretin 5-FU HCT116, HCT-15 - [84]
↓ ATP,
↑ DNA damage
Apoptosis,
↓ PI3K/AKT and NF-κB
Schizandrin 5-FU HCT116, SW480 - [85]
pathways,
↑ miR-195
Apoptosis,
Luteolin OXA HCT116 - [86]
↑ Nrf2 activity
↓ Cell viability and colony
formation,
EGCG 5-FU HCT116, DLD-1 DLD-1 xenograft [87]
apoptosis,
↓ tumor growth
↓ Cell proliferation, DNA
Vine pruning
5-FU HCT116, RKO - effects and cell cycle [88]
residue
modulation
Apigenin 5-FU HCT15 - Apoptosis [89]
↓ Cell proliferation
apoptosis,
↓ radioresistance via the
CT26, Lgr5+ CSC, AOM/DSS-treated BMP signaling pathway,
Polydatin IR [90]
HCT116 mice ↓ CRC proliferation,
↓ tumor number and
volume,
↑ survival
Abbreviations: 5-FU, 5-fluorouracil; IRI, irinotecan; DOX, doxorubicin; OXA, oxaliplatin; VCR, vincristine; mEHT, modulated electro-
hyperthermia; IR, ionizing irradiation; EGCG, epigallocatechin gallate; BPIS, bound polyphenol of inner shell; GEM, gemcitabine. * It is
mentioned in the following text.

4.1.1. Curcumin
Among dietary polyphenols, curcumin is certainly the most studied for combined
therapy against CRC. Curcumin’s anticancer activity has been analyzed in association
with different chemotherapeutic drugs currently used for CRC management both in vitro
and in vivo. Whatever the cell line used, curcumin showed a synergistic effect with the
drug in terms of cell viability. In particular, a considerable reduction in the proliferative
and migratory capabilities and in the apoptotic rates of the metastatic cell line SW620
was observed when 5-FU was combined with curcumin [59]. In this context, curcumin
significantly inhibited phosphoERK (pERK) signaling and downregulated L1 expression,
a cell adhesion molecule correlated with poor prognosis and metastasis. In addition,
curcumin pre-treatment could significantly augment the cytotoxicity of 5-FU on HCT116
and HT29 cell lines and in HCT116 xenografts through the inhibition of autophagy [60],
a cellular adaptation mechanism issued by tumor cells to counteract the cellular stress
induced by chemotherapy [91]. In combination with IRI, curcumin induced cell cycle arrest
and apoptosis in part mediated by ROS generation and the activation of endoplasmic
reticulum (ER) stress in LoVo and HT29 cell lines [61]. Interestingly, on IRI-resistant
LoVo cells, curcumin reduced the expression levels of CSC identification markers and
significantly attenuated chemoresistance through the induction of apoptosis of CSC among
colon cancer cells [62].
The ability of curcumin to reverse chemoresistance has also been described toward
OXA [16]. Long-term application of the drug leads to toxic side effects and resistance,
the major cause of therapy failure. In this context, curcumin increased the apoptotic rate
Cancers 2021, 13, 4499 8 of 17

of chemoresistant CRC and significantly inhibited its migration and invasion potential.
In addition, Yin and coworkers [63] described an increase in caspase 3 activity and a
decrease in the migratory ability of chemoresistant CRC cells through dampening the
TGFβ/Smad2/3 signaling pathway both in vitro and in vivo. Han and coworkers [64],
on the other hand, reported that curcumin can reverse drug resistance in the HCT116 cell
line through its effects on the miRNA-mediated regulation of ERCC1, a key protein of
the nucleotide excision repair (NER) system [92], with alterations in DNA repair ability
being one of the main mechanisms of drug resistance. In another study, human CRC
cell lines containing either mutated or wild-type KRAS were treated with regorafenib, a
multiple kinase inhibitor, in combination with curcumin [65]. The addition of curcumin
to regorafenib augmented apoptosis and autophagy rates in HCT116 (KRAS mutant)
but not in HT-29 cells (KRAS wild-type), thus suggesting that curcumin functions as a
MEK inhibitor to induce a synthetic lethal effect on KRAS-mutant CRC cells receiving
the targeted drug regorafenib. In another study, the exposure of CT26-implanted mice
to curcumin (50 mg/kg for 5 days, oral) and to the PDE5 inhibitor sildenafil (Viagra® )
significantly impaired tumor growth and decreased the expression of PD-L1, PD-L2 [66].
The therapeutic effect was further enhanced by the administration of the anti-PD-1 antibody.
In the same study, curcumin + sildenafil proved effective in combination with a clinically
relevant concentration of 5-FU and caused further activation of DNA damage signaling,
metabolic stress signaling and ER stress signaling [66]. Knocking down ataxia telangiectasia
mutated (ATM), AMP-dependent protein kinase-α (AMPKα), eukaryotic initiation factor
2-α (eIF2α) or LC3-associated phagocytosis (LAP) significantly reduced the lethality of the
combined treatment (curcumin + sildenafil + 5-FU) [66], confirming the involvement of the
above-mentioned pathways. In another study, the capability of curcumin to sensitize CRC
cell lines to gemcitabine (GEM) was investigated in patient-derived cell lines with different
molecular characteristics (CpG island methylator phenotype, CIN and MSI). Treatment
with curcumin plus GEM induced up to 70% biomass reduction in MSI + cell lines and
a fivefold induction of ATM and cyclin-dependent kinase inhibitor 2 (CDKN2) [67]. A
coculture of tumor and immune cells revealed the stimulation of immune-based cytotoxicity
by curcumin in combination with either GEM or the IDO inhibitor indoximod [67].
Although curcumin is one of the most effective phytochemicals, its water solubility,
metabolic instability and poor bioavailability limit its clinical application [93]. Thus,
curcumin analogs have been synthesized, and some of them have been tested in vitro.
Zhao and coworkers [69] analyzed the combined effects of dimethoxycurcumin (DMC),
a lipophilic analog of curcumin, with 5-FU in SW480 and SW620 cell lines, describing an
additive antitumor effect in both cell lines. This effect was closely related to cell cycle arrest
and apoptosis induction as well as to an increase in ROS production, ER expansion and a
decrease in mitochondrial membrane potential. These results are particularly important
since DMC has an increased potential to induce colon cancer cell apoptosis, is less toxic
to normal cells and possesses a higher bioactivity compared to curcumin [94]. In the
same vein, prenylated curcumins that are semisynthetic curcumin derivatives have shown
promising results in in vitro studies of combination therapy. In particular, gercumin
exhibited a synergistic effect when tested in combination with FOLFOX, suppressing
the growth of cancer cells with a potency similar to that of curcumin. Moreover, one of
the combinations tested was also effective at suppressing colonosphere formation [70].
In mice implanted with CT26 tumor cells, oral administration of a nano-formulation of
curcumin and resveratrol (300 mg/kg every 2 days for 2 weeks) in combination with
modulated electro-hyperthermia (mEHT) treatment significantly suppressed tumor growth
and triggered host immunity by recruiting T cells and F4/80+ macrophages into the tumor
mass [71].
Radiotherapy is one of the treatments for CRC. It is important to underline that
polyphenol effects have also been tested in combination with ionizing irradiation (IR). A
combined treatment of curcumin (20 mg/kg, intra-peritoneal (i.p.)) and IR (10 Gy) resulted
in significantly greater tumor growth inhibition and apoptosis compared to IR treatment
Cancers 2021, 13, 4499 9 of 17

alone [68]. Curcumin sensitized cancer cells to IR by altering the expression of DNA
repair-related genes, including DNA ligase IV (LIG4), X-ray repair cross complementing 5
(XRCC5) and polynucleotide kinase/phosphatase (PNK).

4.1.2. Resveratrol
One of the best known polyphenols is resveratrol, a naturally occurring plant antibi-
otic found in various plants, nuts and fruits and especially abundant in grapes and red
wine [95]. Previous studies indicated that resveratrol potentiates the cytotoxic properties of
doxorubicin (DOX), a widely used chemotherapy due to its efficacy against a wide range
of cancers, via downregulation of the MDR1 gene and P-glycoprotein (P-gp) inhibition [96].
In CRC, resveratrol has been shown to suppress TNF-β-induced tumor metastasis and
to chemosensitize CRC cells to 5-FU in 3D alginate cultures [72]. In addition, Khaleel
and coworkers [73] reported the capability of resveratrol to sensitize CRC cells to DOX
via facilitating apoptosis and enhancing the intracellular entrapment of DOX by blocking
the activity of the P-gp pump. Interestingly, the same ability was also demonstrated by
Didox, a synthetic polyphenolic compound that shares important biochemical targets with
resveratrol [97]. Very recently, a novel strategy has been described in which nanoparticles
filled with resveratrol or OXA were applied on in vitro systems. The combination of OXA
and resveratrol nanoparticles exerted a synergistic effect, with a higher cytotoxicity than
the nanoparticle alone or the free drugs, indicating this approach as a promising strategy
for CRC therapy. In mice implanted with CT26 cells, the combination of OXA (8 mg/kg,
intravenous (i.v.)) and resveratrol (30 mg/kg i.v.) every 2 days for 20 days reduced tumor
size and the proportion of tumor-infiltrating myeloid-derived suppressor cells (MDSCs),
thus impairing the immune escape ability of the tumor [74].

4.1.3. Other Dietary Polyphenols

Quercetin is a major constituent of various dietary products whose cancer preven-
tion and treatment potentials have been extensively explored [98,99]. A combination
of quercetin and IR exhibited dramatic anticancer effects by targeting colon CSC and
inhibiting Notch-1 signaling in vitro [75]. These effects were also confirmed in vivo in
HT-29 xenografts receiving quercetin (10 mg/kg/day s.c.) and/or radiation (5 Gy/week)
treatment for four weeks. The combined treatment significantly reduced tumor volume
compared to controls and induced a remarkable decrease in CSC markers and Notch-1
signaling protein expression [75]. Although quercetin possesses great medicinal value,
its use as a therapeutic agent is hampered by its poor oral bioavailability. The loading of
quercetin onto self-assembling lecithin-stabilized polymeric micelles (LsbPMs) provided a
greater stability of hydrophobic chemicals and an enhanced bioavailability as compared
to free quercetin [76]. A combination of DOX (4 and 2 mg/kg i.v.) with this quercetin
formulation (50 mg/kg i.v.) resulted in an efficient growth inhibition of CT26 colon cancer
cells and reduced cardiotoxicity in vivo [76].
Bound polyphenol of inner shell (BPIS) from foxtail millet bran displayed effective
antitumor activities in vitro and in vivo. BPIS significantly increased the sensitivity of
human drug-resistant CRC cell lines to OXA. Of particular relevance is the ability to
reverse the multidrug resistance of CRC when cells exposed to 5-FU, OXA and vincristine
(VCR) are pretreated with BPIS. The inhibition of cell proliferation, the promotion of
cell apoptosis and the accumulation of rhodamine-123 (Rh-123) in HCT-8/Fu cells are
among the mechanisms exploited by BPIS to synergize with chemotherapy [77]. More
recently, remodeling of ganglioside GM3 catabolism [78] and upregulation of the miR-
149 expression [79] have been proposed as mechanisms underlying the reversal effect of
polyphenols on cancer drug resistance.
In an attempt to find molecules to prevent the emergence of drug resistance, Riahi-
Chebbi and coworkers [80] recently investigated the antitumoral effect of thirteen phenolic
compounds, from the Tunisian quince (Cydonia oblonga Miller), on the human 5-FU-resistant
LS174-R CRC cells either as monotherapy or in combination with 5-FU. Only kaempferol
Cancers 2021, 13, 4499 10 of 17

was able to chemosensitize 5-FU-resistant LS174-R cells, exerting a synergistic inhibitory

effect on cell viability. Kaempferol has already shown anticancer effects in several cancer
cell lines, while exhibiting almost no or minor toxicity against normal epithelial, peripheral
blood and myeloid cells [100,101]. A combination of kaempferol with 5-FU impacted on dif-
ferent cellular effectors, finally enhancing apoptosis and cell cycle arrest [80]. In particular,
this combination blocked the production of ROS; modulated the expression of JAK/STAT3,
MAPK, PI3K/AKT and NF-κB [80]; and increased levels of the pro-apoptotic protein Bax
while downregulating the anti-apoptotic protein Bcl-2 and thymidylate synthase [81], an
enzyme involved in DNA replication.
Silybin, a flavonoid extracted from the milk thistle seeds of Silybum marianum, has been
used in an attempt to limit regorafenib’s side effects, thus improving its tolerability and
enhancing its clinical activity. Regorafenib is a very promising drug for chemorefractory
mCRC patients, but its toxicity profile has limited its use in clinical practice. A combined
treatment of silybin and regorafenib induced, in a panel of human colon cancer cell lines
with distinct mutations in the KRAS, NRAS, BRAF, and PIK3CA genes, synergistic anti-
proliferative and apoptotic effects via the inhibition of the PI3K/AKT/mTOR pathway and
the production of ROS within cells [82].
In recent years, propolis has raised great interest due to a variety of pharmacological
effects, including anticancer properties [102]. Propolis consists of a mixture of different
compounds, including polyphenols, whose composition depends on the geographical site
of production [102,103]. Administering an alcoholic extract of propolis (10, 30 or 90 mg/kg
i.p., 5 times a week) rich in chrysin, galangin and pinocembrin in combination with 5-FU
(50 mg/kg, once a week) for 8 weeks in AOM/DSS-induced CRC reduced the number of
pathological lesions in comparison with 5-FU-based monotherapy through decreasing the
expression of β-catenin, iNOS and COX-2 proteins in the intestinal tissue [83].
Several other polyphenolic compounds have been used in combination with 5-FU
or OXA in in vitro assays, to potentiate its activity and to reduce the side effects, in an
attempt to improve the therapeutic potential of the treatment. In this context, studies
have been reported on tangeretin [84], schizandrin [85], luteolin [86], epigallocatechin
gallate (EGCG) [87], the ohmic extract of vine pruning residue (VPE) [88] and even on dual
drug loaded liposomes bearing apigenin and 5-FU [89]. These investigations reported an
increase in the cytotoxic activity of 5-FU or OXA in combined exposure by stimulating
different mechanisms influencing the life and death of the cells. Polydatin, a glycoside of
resveratrol, decreased the radioresistance of colorectal CSC via the BMP signaling pathway,
thereby sensitizing tumor cells to radiotherapy [90].
To summarize, the studies herein described provide evidence that combining treat-
ments of natural polyphenols with anticancer drugs is a promising strategy able to improve
the effectiveness of treatment and to overcome drug resistance.

4.2. Data from Clinical Trials

In light of the evidence obtained in preclinical models, a clinical trial evaluation is
mandatory for translation into humans and to further validate the feasibility and efficacy
of such natural product formulations for their use in a clinical setting. Of note, a de-
creased total antioxidant capacity associated with a progressive reduction in polyphenol
plasma levels has been described in stage II–IV CRC patients, with significantly lower
values in subjects undergoing therapy with cytostatic drugs, alone or in combination with
monoclonal antibodies [104].
As stated above, the efficacy of 5-FU-based chemotherapy in advanced, inoperable
CRC patients is limited due to its intolerable adverse effects. A number of human studies
have been registered with the aim of evaluating the adjuvant potential of polyphenols
(mainly phenolic acids and flavonoids) to standard treatments for advanced/mCRC. How-
ever, to date, only a few of them have reported the outcome (Table 2), possibly due to still
on-going investigations or discontinuation of the studies.
Cancers 2021, 13, 4499 11 of 17

Table 2. Clinical studies evaluating the effects of polyphenols and standard therapy combination in CRC patients.

Polyphenol (Dose) Subjects/Study Type Experimental Group Control Group Main Outcome Refs/Trial
Stage IV mCRC ↑ PFS Clinicaltrials.gov
Curcumin (C3 pts/Phase IIa FOLFOX + Curcumin ↑ OS = QOL (last accessed in June
FOLFOX (n = 9)
complexed, 2 g/day) randomized (CUFOX, n = 18) ↓ neuropathy scores 2021) NCT01490996
controlled (trend) (completed) [83,84]
Clinicaltrials.gov
Curcumin
Stage IV mCRC (last accessed in June
(nanostructured lipid FOLFIRI/Bevacizumab
pts/Interventional None In progress 2021) NCT02439385
particles, 100 mg + Curcumin (n = 50)
Phase II (recruitment
twice/day)
completed, 2020)
Clinicaltrials.gov
FOLFOX + Genistein
Stage IV mCRC (last accessed in June
Genistein (60 (n = 10) ↑ RR
pts/Interventional None 2021) NCT01985763
mg/day) FOLFOX/Bevacizumab ↑ PFS
Phase I/II Pilot (completed, 2018)
+ Genistein (n = 3)
[87]
www.irct.ir (last
Stage II/III CRC OXA infusion/oral OXA infusion/oral
↓ serum CRP, IL-8, accessed in June 2021)
Fisetin (100 mg/day) pts/Randomized CAPE + Fisetin CAPE + placebo
MMP-7 IRCT2015110511288N9
placebo controlled (n = 18) (corn starch, n = 19)
[89]
↑ PFS
Silybin (188 mg/day, Pre-treated advanced
Regorafenib + Silybin ↑ OS
complexed with PC mCRC None [75]
(n = 22) ↓ drug-induced liver
and vitamin E) pts/Prospective Pilot
damage
Abbreviations: pts, patients; FOLFOX, 5-fluorouracile, folinic acid and oxaliplatin; CUFOX, FOLFOX + curcumin; OXA, oxaliplatin; CAPE,
capecitabine; PC, phosphatidylcholine; PFS, progression-free survival; OS, overall survival; RR, response rate; QOL, quality of life; CRP,
C-reactive protein.

The CUFOX trial was the first study that combined daily oral curcumin with FOLFOX-
based chemotherapy in subjects with a histological diagnosis of mCRC [105]. A phase I
dose-escalation study was designed to determine the acceptable target dose of curcumin
in order to safely proceed to a phase IIa open-labeled randomized controlled trial. The
addition of daily oral curcumin to standard chemotherapy turned out to be safe and
tolerable. No significant difference between FOLFOX and CUFOX (FOLFOX plus curcumin)
arms was reported in terms of quality of life or neurotoxicity [106]. However, an increase
in the median progression-free survival (PFS) and overall survival (OS) was achieved in
CUFOX-treated patients with respect to the control group [106].
The clinical application of curcumin is greatly restricted due to its low water solubil-ity,
poor oral absorption and rapid metabolism, and a number of curcumin nanoformula-tions
have been developed to overcome these limitations. To date, three clinical trials on the use
of curcumin nanoformulations in CRC and colorectal adenomatous polyposis have been
registered in the ClinicalTrials.gov (last accessed on July 2021) database [54]. Among them,
a phase II study was designed to investigate nanostructured lipid curcumin particles as a
dietary supplement in combination with FOLFIRI/bevacizumab-based chemotherapy in
patients with unresectable CRC liver metastases. The study included a two-year follow-up
after the intervention for PFS and OS, with safety, quality of life and fatigue as secondary
outcomes. However, no information on the outcome has been reported yet. More gener-
ally, although promising results have been generated from preclinical studies, only poor
evidence has been provided that combining curcumin with chemotherapeutic agents is
effective for treating cancer in humans [107].
Epidemiological and preclinical studies have demonstrated a role for genistein, a
soy-derived isoflavon whose safety in humans has been well established, in colorectal
malignancy prevention and treatment [56]. Recently, the first-in-human study of genistein
in combination with FOLFOX or FOLFOX/bevacizumab therapy was approved for the
upfront treatment of mCRC [108]. Subjects received up to six cycles of therapy every
2 weeks in combination with oral genistein. Therapy-responsive patients went on to
complete six additional cycles or underwent surgical resection when feasible. The response
rate and PFS obtained in this pilot study were substantially better than those previously
Cancers 2021, 13, 4499 12 of 17

reported for chemotherapy alone [109], suggesting that the combination treatment can
improve efficacy.
A different flavonoid, fisetin, was studied for its potential adjuvant effect on CRC
therapy, in virtue of its strong anti-inflammatory acitvity. Specifically, a clinical study
was designed with the aim of assessing the efficacy of fisetin supplementation on the
inflammatory status and matrix metalloproteinase (MMP) levels in CRC patients who
had undergone primary tumor resection two weeks prior to the intervention [110]. In this
double-blinded, randomized placebo-controlled clinical trial, stage II and III CRC patients
undergoing chemotherapy (OXA infusion plus oral capecitabine) were assigned to receive
either fisetin or placebo for seven consecutive weeks. Despite the short supplementation
period, this study highlighted a beneficial effect of fisetin on patient inflammatory status,
with a significant decrease in serum levels of C-reactive protein, IL-8 and MMP-7. This
study also paved the way toward future clinical investigations aimed at determining the
more specific effects of this flavonoid compound on disease outcome.
Polyphenols have also been explored for their possible use in CRC patients with
progressive disease due to unresponsiveness to standard chemotherapies. In a prospective
proof of concept study, mCRC patients were treated with regorafenib in combination with a
complex of silybin, vitamin E and phospholipids, after failure of all available therapies [82].
In this formulation, silybin was found to increase the clinical efficacy and tolerability of
regorafenib, leading to increased PFS and OS [82]. Silybin combined with regorafenib was
suggested as a promising strategy to improve the efficacy of this recently approved drug,
whose toxicity has limited its use in clinical practice.
The idea that polyphenols can act as adjuvants to CRC therapy is strongly supported
by the evidence found in human studies. However, future studies involving a larger
number of subjects and including control groups are recommended to move toward
clinical application.

5. Conclusions
CRC is one of the deadliest types of cancer worldwide. By 2030, the mortality rate of
CRC is expected to increase by 60%. Therapy failure, due to low efficacy, heavy adverse
effects and drug resistance, is a major concern. Although dietary polyphenols have been
extensively investigated for their chemopreventive and direct anticancer effects on CRC, the
idea of using polyphenols in combination with standard treatments to increase efficacy and
cope with therapy toxicity is extremely intriguing. Chemo-/radio-sensitization, autophagy
inhibition, the harnessing of migration and immunomodulation are the key mechanisms
ascribed to dietary polyphenols in combination with current CRC treatments to date.
Nevertheless, the multiplicity of cell targets and molecular pathways activated by dietary
polyphenols will require a careful preclinical evaluation of the host health status, disease
stage and of the companion drugs before clinical translation.
The bioavailability and bioactivity of polyphenols are also critical issues, which largely
rely on their formulation and on inter-individual variability. Differences in absorption,
distribution and metabolism, as well as age, sex, genetics and epigenetic factors, all con-
tribute to the inter-individual variability of response to polyphenols. It is worth noting
that dietary polyphenols and/or their metabolites are present at low concentrations in
the cells. If administered at very high concentrations, polyphenols may cause toxic ef-
fects. Indeed, adverse effects of polyphenols have been reported in some experimental
studies [111,112], although it has not always been proven that these effects also occur in
humans. In addition, the co-administration of natural products along with conventional
medicines can modify their bioavailability and toxicity profile. Therefore, the vigilance
for their potential dose-related toxicity should remain high. In addition, in virtue of their
antioxidant properties, polyphenols may, on one hand, alleviate the adverse effects of
chemotherapy and/or radiotherapy and, on the other hand, antagonize oxidative damage
induced by these treatments. Studies on animal models have started to address these
issues by exploring the best dosage, route of administration and formulation to optimize
Cancers 2021, 13, 4499 13 of 17

anticancer effects and minimize the detrimental effects on companion drugs. However, it
is necessary to take into account that a beneficial dose in an animal model can be harmful
when applied in a human setting. Alternatively, a dose used in an experimental study may
never occur in humans because the bioavailability is very low or because the appropriate
dose never reaches the target site.
While surgery and chemo- and radio-therapy interventions continue to represent
essential treatments of CRC depending on the tumor stage, the experimental evidence
reported herein highlights the enormous potential of dietary polyphenols as adjuvants
of current anticancer strategies and paves the way for the further development of these
compounds in the optimal therapeutic management of CRC patients.

Author Contributions: L.B., A.F., M.D.C. and L.C. contributed to conceptualization and writing of
the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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