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Citation: Esquivel-Chirino, C.;
Bolaños-Carrillo, M.A.;
Carmona-Ruiz, D.; Lopéz-Macay, A.;
Hernández-Sánchez, F.;
Montés-Sánchez, D.;
Escuadra-Landeros, M.;
Gaitán-Cepeda, L.A.;
Maldonado-Frías, S.; Yáñez-Ocampo,
B.R.; et al. The Protective Role of
Cranberries and Blueberries in Oral
Cancer. Plants 2023,12, 2330.
https://doi.org/10.3390/plants
12122330
Academic Editor: Milena Popova
Received: 17 May 2023
Revised: 8 June 2023
Accepted: 10 June 2023
Published: 15 June 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
plants
Review
The Protective Role of Cranberries and Blueberries in
Oral Cancer
César Esquivel-Chirino 1, *, Mario Augusto Bolaños-Carrillo 2, Daniela Carmona-Ruiz 3, Ambar Lopéz-Macay 4,
Fernando Hernández-Sánchez 5, Delina Montés-Sánchez 6, Montserrat Escuadra-Landeros 7,
Luis Alberto Gaitán-Cepeda 8, Silvia Maldonado-Frías 9, Beatriz Raquel Yáñez-Ocampo 10,
JoséLuis Ventura-Gallegos 11, Hugo Laparra-Escareño 12 , Claudia Patricia Mejía-Velázquez 13
and Alejandro Zentella-Dehesa 11, 14
1Área de Básicas Médicas, División de Estudios Profesionales, Facultad de Odontología,
Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
2Área de Ciencias Naturales, Departamento de Bachillerato, Universidad del Valle de México,
Campus Guadalajara Sur, Guadalajara 045601, Mexico; mario_bolanos@my.uvm.edu.mx
3Área de Ortodoncia, División de Estudios Profesionales, Facultad de Odontología,
Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
4
Laboratorio de Liquído Sinovial, Instituto Nacional de Rehabilitación LGII, Ciudad de México 14389, Mexico
5Departamento de Virología y Micología, Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío
Villegas”, Ciudad de México 04502, Mexico
6Investigación Biomédica Básica, Licenciatura en Estomatología, Benemérita Universidad Autónoma de
Puebla, Puebla 75770, Mexico
7Facultad de Odontología, Universidad Intercontinental, Ciudad de México 14420, Mexico
8Departamento de Medicina y Patología Oral Clínica, División de Estudios de Posgrado e Investigación,
Facultad de Odontología, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
9Laboratorio de Bioingeniería de Tejidos, División de Estudios de Posgrado e Investigación,
Facultad de Odontología, Universidad Nacional Autónoma de México, Ciudad de México 04360, Mexico;
sylvymaf@comunidad.unam.mx
10 Especialidad en Periodoncia e Implantología, División de Estudios de Posgrado e Investigación,
Facultad de Odontología, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
11 Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas,
UNAM, Ciudad de México 04510, Mexico
12 Departamento de Cirugía, Sección de Cirugía Vascular y Terapia, Instituto de Ciencias Médicas y Nutrición
Salvador Zubirán, Ciudad de México 14080, Mexico
13 Departamento de Patología, Medicina Bucal y Maxilofacial, Facultad de Odontología,
Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
14 Unidad de Bioquímica, Instituto de Ciencias Médicas y Nutrición Salvador Zubirán,
Ciudad de México 14080, Mexico
*Correspondence: seminarioinvestigacion@fo.odonto.unam.mx; Tel.: +52-55-5109-8656
Abstract:
Background: Oral cancer has a high prevalence worldwide, and this disease is caused
by genetic, immunological, and environmental factors. The main risk factors associated with oral
cancer are smoking and alcohol. Results: There are various strategies to reduce risk factors, including
prevention programs as well as the consumption of an adequate diet that includes phytochemical
compounds derived from cranberries (Vaccinium macrocarpon A.) and blueberries (Vaccinium corymbo-
sum L.); these compounds exhibit antitumor properties. Results: The main outcome of this review is
as follows: the properties of phytochemicals derived from cranberries were evaluated for protection
against risk factors associated with oral cancer. Conclusions: The secondary metabolites of cranberries
promote biological effects that provide protection against smoking and alcoholism. An alternative for
the prevention of oral cancer can be the consumption of these cranberries and blueberries.
Keywords:
oral cancer; oral squamous carcinoma cell (OSCC); phytochemicals; berries; flavonoids;
flavanols; cranberries; blueberries
Plants 2023,12, 2330. https://doi.org/10.3390/plants12122330 https://www.mdpi.com/journal/plants
Plants 2023,12, 2330 2 of 23
1. Background
Cancer is a disease characterized by the proliferation of tumor cells, followed by the
invasion of distant organs (metastasis), and can cause serious health complications, often
leading to the death of the patient [
1
–
5
]. According to statistics from 2020, approximately
10 million people in the world died from cancer, and one in every six deaths was attributed
to this disease. A significant percentage of cases correspond to oral cancer, which affects
anatomical regions, such as the base of the tongue, lip, gingiva, tonsil, floor of the mouth,
and uvula [6–8]. Oral cancer accounts for 85% of neoplasms in the oral cavity [9].
Approximately 90% of oral cancers correspond to oral squamous cell carcinoma, while
the remaining 10% are classified as melanomas, sarcomas, minor salivary gland carcinomas,
or metastatic carcinomas [
10
]. Oral cancer survival is reported to average five years [
11
,
12
].
The cause of oral cancer involves several factors, including genetic, environmental, immuno-
logical, and viral infections, and contact mainly with tobacco and alcohol consumption [
6
].
An inadequate daily diet, especially a low consumption of fruits and vegetables, is another
important factor associated with cancer progression [
13
,
14
]. A balanced diet should include
compounds derived from plant and fruit extracts, such as phytochemicals, phenolics, and
flavonoids, to obtain their antioxidant and protective properties against various risk factors,
as well as their antitumor effects [
15
–
17
]. Furthermore, the use of phytochemicals has been
identified as a possible protective factor against oral cancer, particularly in fruits of the
Ericaceae family, such as cranberries and blueberries [18].
Berries contain phytochemical compounds with biological activity, such as flavanols,
ellagitannins, gallotannins, proanthocyanidins, and anthocyanins [
15
–
17
]. The antioxidant
and antitumor properties of berry phytochemicals have been shown
in vitro
and
in vivo
in
oral cancer models [
17
–
21
]. The aim of this work is to investigate the antioxidant activities
of berry and cranberry phytochemicals in protecting the oral mucosa against oral cancer
risk factors.
2. Materials and Methods
A comprehensive literature search was conducted from March 2000 to March 2023.
Keyword searches were conducted in databases, such as PubMed, EBSCO, Wiley, and
SpringerLink, using terms, such as “oral cancer,”, “berries”, “oral cancer and berries”,
“phytochemicals and oral cancer”, and “cranberries and oral cancer.” Articles were selected
if they contained information about phytochemicals and cancer. Studies that mentioned
effects on other types of cancer were also included. The exclusion criteria were articles that
were not written in English and articles from popular science journals and dissertations.
3. Introduction
3.1. Head and Neck Cancer
This neoplasm involves the oral cavity, larynx, oropharynx, and paranasal sinuses
(Figure 1) [21,22].
Plants 2023, 12, x FOR PEER REVIEW 3 of 26
Figure 1. Head and neck cancer distribution. Created with BioRender.com (accessed on 10 March
2022)
3.2. Oral Cancer
Oral cancer is defined as a malignant neoplasm that can manifest in any part of the
oral cavity [21]. The most frequent anatomical sites for oral cancer are the tongue (includ-
ing the base and anterior part), gums, tonsils, oropharynx, lips, floor of the mouth, soft
and hard palate, oral mucosa, and salivary glands (Figure 2) [22].
Figure 2. Distribution of oral cancer. Created with BioRender.com (accessed on 10 March 2022).
3.3. Epidemiology
Oral cancer represents the sixth-highest prevalence of malignant neoplasms in the
developed world; however, it is the eighth most-prevalent malignant neoplasm in less-
developed countries [23]. During 2020, 377,713 new cases of oral cancer were diagnosed
worldwide, and of those cases, 177,757 resulted in death [24,25]. A retrospective study
conducted between 1990 and 2019 reported that Asia had the highest number of oral can-
cer cases, followed by North America, South America, and Europe [26]. Oral cancer is 3.6
times more frequent among men than women, with higher mortality rates in underdevel-
oped countries [27].
3.4. Etiology and Risk Factors
The cause of oral cancer involves multiple factors; however, the main risk factors are
tobacco and alcohol consumption [7,28]. Several risk factors have been identified for oral
cancer, including viral infections, especially human papillomavirus (HPV), immunosup-
pression, genetic predisposition, poor oral hygiene, and an inadequate diet [26,27,29]. An-
other important factor associated with oral cancer is chronic inflammatory processes, such
as periodontal disease [30,31].
Figure 1.
Head and neck cancer distribution. Created with BioRender.com (accessed on 10
March 2022).
Plants 2023,12, 2330 3 of 23
3.2. Oral Cancer
Oral cancer is defined as a malignant neoplasm that can manifest in any part of the
oral cavity [
21
]. The most frequent anatomical sites for oral cancer are the tongue (including
the base and anterior part), gums, tonsils, oropharynx, lips, floor of the mouth, soft and
hard palate, oral mucosa, and salivary glands (Figure 2) [22].
Plants 2023, 12, x FOR PEER REVIEW 3 of 26
Figure 1. Head and neck cancer distribution. Created with BioRender.com (accessed on 10 March
2022)
3.2. Oral Cancer
Oral cancer is defined as a malignant neoplasm that can manifest in any part of the
oral cavity [21]. The most frequent anatomical sites for oral cancer are the tongue (includ-
ing the base and anterior part), gums, tonsils, oropharynx, lips, floor of the mouth, soft
and hard palate, oral mucosa, and salivary glands (Figure 2) [22].
Figure 2. Distribution of oral cancer. Created with BioRender.com (accessed on 10 March 2022).
3.3. Epidemiology
Oral cancer represents the sixth-highest prevalence of malignant neoplasms in the
developed world; however, it is the eighth most-prevalent malignant neoplasm in less-
developed countries [23]. During 2020, 377,713 new cases of oral cancer were diagnosed
worldwide, and of those cases, 177,757 resulted in death [24,25]. A retrospective study
conducted between 1990 and 2019 reported that Asia had the highest number of oral can-
cer cases, followed by North America, South America, and Europe [26]. Oral cancer is 3.6
times more frequent among men than women, with higher mortality rates in underdevel-
oped countries [27].
3.4. Etiology and Risk Factors
The cause of oral cancer involves multiple factors; however, the main risk factors are
tobacco and alcohol consumption [7,28]. Several risk factors have been identified for oral
cancer, including viral infections, especially human papillomavirus (HPV), immunosup-
pression, genetic predisposition, poor oral hygiene, and an inadequate diet [26,27,29]. An-
other important factor associated with oral cancer is chronic inflammatory processes, such
as periodontal disease [30,31].
Figure 2. Distribution of oral cancer. Created with BioRender.com (accessed on 10 March 2022).
3.3. Epidemiology
Oral cancer represents the sixth-highest prevalence of malignant neoplasms in the
developed world; however, it is the eighth most-prevalent malignant neoplasm in less-
developed countries [
23
]. During 2020, 377,713 new cases of oral cancer were diagnosed
worldwide, and of those cases, 177,757 resulted in death [
24
,
25
]. A retrospective study
conducted between 1990 and 2019 reported that Asia had the highest number of oral cancer
cases, followed by North America, South America, and Europe [
26
]. Oral cancer is 3.6 times
more frequent among men than women, with higher mortality rates in underdeveloped
countries [27].
3.4. Etiology and Risk Factors
The cause of oral cancer involves multiple factors; however, the main risk factors
are tobacco and alcohol consumption [
7
,
28
]. Several risk factors have been identified for
oral cancer, including viral infections, especially human papillomavirus (HPV), immuno-
suppression, genetic predisposition, poor oral hygiene, and an inadequate diet [
26
,
27
,
29
].
Another important factor associated with oral cancer is chronic inflammatory processes,
such as periodontal disease [30,31].
3.4.1. Tobacco
The use of tobacco products is the principal cause of more than 8 million cancer deaths
worldwide [
32
]. Tobacco products have different carcinogenic properties [
33
]. People who
smoke have a predisposition to oral cancer that is between seven and ten times higher
than that of nonsmokers, although the level of exposure depends on the frequency and
duration of smoking [
34
–
37
]. The most common carcinogens in tobacco are benzopyrenes,
4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone, and N
0
-nitrosonornicotine (NNN) [
38
,
39
].
The metabolites of these compounds present in tobacco induce mutations that affect DNA
replication and the genes involved in the control of cell growth, favoring damage to the
oral mucosa and malignant transformation [
40
,
41
]. In Asia, a form of smokeless tobacco
called Guthka is consumed, which is a mixture of betel nut (Areca catechu), tobacco, and
spices. This preparation is popular among the young population due to its stimulating,
relaxing effects [
42
]. However, betel nut contains tannins and alkaloids, such as arecoline,
which have negative effects on health and have been associated with oral cancer [
30
,
42
].
Tobacco products have carcinogenic and genotoxic effects on epithelial cells and are related
to pancreatic cancer, cardiovascular disease, periodontal conditions, and asthma [
31
]. In
addition, tobacco consumption can contribute to the development of esophageal carci-
noma [
43
]. Tobacco products generate reactive oxygen species (ROS), change pH, and cause
Plants 2023,12, 2330 4 of 23
mucosal irritation, activating T cells as well as macrophages, which promote prostaglandin
production and hyperplasia [
40
]. These types of irritants and subsequent inflammation are
important promoter events in the progression to malignant transformation.
3.4.2. Alcohol
Alcohol consumption is a recognized factor in the development of oral and oropha-
ryngeal cancer [
12
,
40
]. The main metabolite of alcohol is acetaldehyde, which is involved
in DNA synthesis and repair and induces, among many other effects, the exchange of sister
chromatids and mutations [
40
,
41
]. Alcohol acts as a local irritant chemical when in contact
with the oral mucosa. Therefore, by dissolving and damaging the lipids of the epithelium,
alcohol consumption increases the permeability of the oral mucosa [
44
]. Frequent alcohol
consumption is associated with impaired innate and acquired immunity, which increases
the susceptibility of the oral cavity to infections and neoplasms [
45
]. Alcohol is metabolized
by enzymes, such as dehydrogenase, cytochrome P-4502 E1, and catalases, generating
acetaldehyde. This metabolite has carcinogenic and genotoxic properties [
46
]. In addition,
the consumption of alcohol activates inflammatory processes since inflammatory white
cells are recruited and various interleukins are produced, which causes the formation of
ROS [
47
]. It has been reported that the consumption of 10 g or more of alcohol per day
has been related to a 15% increased risk of having oral cancer and a 10% increased risk of
having pharyngeal cancer [
48
]. Oral squamous cell carcinoma is related to polymorphisms
of the ALDH2 gene [
49
]. Alcohol and tobacco use increase the risk of oral cancer up to
five-fold [50–52].
3.4.3. Viral Infections
The major viral infections associated with oral cancer include human herpesvirus
and human papillomavirus (HPV) [
53
,
54
]. These viruses cause genetic instability through
mutations, aberrations, and DNA damage [55].
Human Papillomavirus
HPV is the virus most frequently associated with cases of oral cancer [
56
]. HPV
genotypes 16 and 18 are the most frequently associated with oral cancer. HPV encodes two
oncoproteins, E6 and E7, which bind to p53 and Rb proteins, causing the loss of regulation
of DNA replication, repair, and apoptosis [57].
Epstein–Barr Virus
This virus presents double-stranded DNA with oncogenic potential and has been
considered the causal agent of several neoplasms, including squamous oral cell carcinoma
(OSCC) [
58
]. In 1997, this virus was recognized as the cause of nasopharyngeal carcinoma
and has also been associated with Hodgkin lymphoma, NK cell lymphoma, and gastric car-
cinoma [
59
]. People infected with Epstein–Barr virus have a 2.5-fold increased probability
of acquiring OSCC. However, the direct association between OSCC and Epstein–Barr virus
is not completely clear [60].
3.4.4. Oral Health
Poor oral hygiene can affect the oral microbiota by allowing bacteria to evade the
host immune response and increase their growth, which can cause a shift from symbiosis
to dysbiosis [
61
]. In addition, an increased amount of endogenous nitrosamine, a major
carcinogen, is produced, which may pose a risk for oral cancer initiation [
50
]. A report
found that, in patients with inadequate mouth hygiene, there was a seven-fold increased
risk of developing oral cancer [
51
]. In addition, tooth fractures, tooth decay, and poorly
fitting dentures can cause chronic irritation of the oral mucosa, which, in combination
with other factors, such as smoking or drinking alcohol, may promote the occurrence of
oral cancer [
62
]. Another relevant factor is the use of mouthwashes containing alcohol
as a solvent or preservative in combination with tobacco or alcohol consumption [
63
,
64
].
Plants 2023,12, 2330 5 of 23
However, there are no conclusive data to suggest an increased risk of oral cancer from the
use of these mouthwashes alone.
3.4.5. Diet and Nutrition
Several studies have found that low fruit and vegetable consumption may contribute
to the increased risk of developing oral cancer [
65
]. A high body mass index (BMI) has been
implicated in an elevated risk of developing oral cancer [
66
]. It is important to analyze the
relationship between food consumption and the risk of oral cancer. To date, it is consid-
ered that an adequate diet should include the consumption of phytochemicals, phenolics,
and flavonoids that have antioxidant and antitumor properties [
16
–
18
]. In addition, the
consumption of phytochemicals has been reported to have protective effects against risk
factors associated with oral cancer [
18
]. Therefore, it is recommended to consume foods
that contain a significant concentration of phytochemicals, such as berries, the consumption
of which has been related to a reduction in oxidative stress and inflammation [16].
3.5. Premalignant Lesions
One area of opportunity remains the early detection of oral cancer. Therefore, the
development of programs and strategies for the early detection of premalignant lesions may
improve patient survival and prognosis [
67
]. Therefore, a detailed patient history and a
thorough clinical examination are essential [
16
]. Oral cancer patients have no symptoms in
the early stages, leading to diagnosis in advanced stages [
61
]. Prevention programs should
guide oral health professionals to search for and identify precancerous lesions. The most
common premalignant lesions are leukoplakia, erythroplakia, and oral lichen planus [68].
3.5.1. Leucoplakia
Leucoplakia is characterized by white spots or plaques that are not scraped off. In
the clinical diagnosis, leukoplakia must be differentiated from other lesions, such as lichen
planus, candidiasis, friction keratosis, smoker’s keratosis, nicotinic and uremic stomatitis,
leukoedema, and hairy leukoplakia [
68
]. Leucoplakia has been reported to have a malignant
transformation rate between 1 and 5%; however, studies suggest that it may have a chance
of dysplasia or invasive carcinoma [69,70].
3.5.2. Erythroplasia
Erythroplasia is characterized by the presence of a red patch or spot. It is considered a
high-risk lesion for malignancy and must be differentiated from erythematous candidiasis,
erythema migrans, lichen planus lesions, lupus, and other erosive lesions [
71
,
72
]. In contrast
to leukoplakia, erythroplakia is more than 90% likely to have dysplasia or carcinoma
in situ [73].
3.5.3. Lichen Planus
Lichen planus is an inflammatory disease from an unclear cause that presents as white
reticular lesions that may be associated with atrophic, erosive, ulcerative, and plaque-like
areas [
74
]. The pathophysiology of lichen planus begins with an autoimmune response
mediated by T lymphocytes that causes alterations in the basal cells of the epithelium,
generating an inflammatory infiltrate in the basement membrane and leading to subsequent
complications [75].
3.6. Histological Aspects of Oral Cancer
Oral cancer presents various degrees of histological differentiation. Histologic features
include (1) loss of basement membrane and stratum basal structure, (2) increased number
of mitoses, and (3) invasion of the underlying connective tissue [
75
,
76
]. Oral cancer is the
result of genetic and epigenetic changes that lead to histological changes, all associated
with a malignant transformation of the epithelium [
77
,
78
]. It is an invasive neoplasm that
has a poor prognosis and can develop metastases in distant organs. Oral cancer metastases
Plants 2023,12, 2330 6 of 23
spread primarily through the submandibular, cervical, and jugular lymph nodes. Distant
metastasis spreads to the jaw and finally to the lungs, which compromises the health of
the patient and has a higher risk of death [17–20]. Investigating and identifying the major
mechanisms involved in oral carcinogenesis is therefore important.
3.7. Carcinogenesis of Oral Cancer
Carcinogenesis is a process that involves the alteration of molecular function, changes
in cell morphology, and epithelial, connective tissue, and immune function. As a result of
this process, cells acquire new functions that allow them to survive and proliferate [
79
].
Carcinogenesis comprises three phases: initiation, promotion, and progression. During
initiation, endogenous and exogenous factors generate molecular defects, such as mutations,
chromosomal abnormalities, and epigenetic alterations [
80
]. The initiation phase continues
through the promotion phase, which is characterized by the selective proliferation of tumor
cells with stem cell characteristics. Then, the progression phase continues, in which tumor
cells act on their tumor microenvironment to create conditions that favor cell proliferation
and survival [
81
]. In the carcinogenesis of oral cancer, oncogenes and tumor suppressor
genes and their associated epigenetic alterations play an important role [82].
3.7.1. Oncogenes and Tumor Suppressor Genes
Proto-oncogenes encode the proteins that regulate cell division and differentiation
and activate oncogenes through DNA mutations and the inactivation of tumor suppressor
genes [
83
]. Various oncogenes have been implicated in oral cancer development, including
the epidermal growth factor receptor (EGFR/c-erb 1), members of the Ras gene family,
c-myc, int-2, hst-1, PRAD-1, and bcl-1 [
84
]. Gain-function mutations of these oncogenes
facilitate the appearance of neoplastic transformation. On the other hand, tumor suppressor
genes participate in oral carcinogenesis and their alteration indicates the onset of a neoplas-
tic transformation. Tumor suppressor genes associated with oral cancer include: (1) cell
cycle genes (TP53, CDKN2A, and Rb1), (2) genes related to the tumor microenvironment,
(3) adhesion molecules, and (4) DNA repair genes and genes associated with apoptosis [
84
].
3.7.2. Epigenetic Alterations
DNA methylation mechanisms and histone code modifications may contribute to
tumor development and neoplastic transformation [
85
]. Aberrant hypermethylation of the
promoter regions of tumor suppressor genes disrupts the binding of a transcription factor,
causing the genes to be silenced and promoting uncontrolled cell proliferation. The p16
protein, whose gene is located at the CDKN2A locus, is no longer expressed in 50–75%
of oral cancer patients [
86
]. The absence of its expression is related to the methylation of
the promoter of this gene, which affects the expressions of p15 and p14, two inhibitors of
cyclin/CDK complexes. Gene silencing has also been detected in patients with oral cancer
associated with DNA repair, apoptosis, the Wnt signaling pathway, and E-cadherin [86].
Histones are structural proteins that form a complex with DNA, and the acetylation
or methylation of these proteins induces conformational changes in DNA that regulate
transcription [87–89].
4. Treatment
Oral cancer treatment focuses on eradicating the tumor, preserving or restoring the
shape and function of the mouth, preventing recurrence, and reducing the mortality
rate while increasing the quality of life of the patient [
21
–
23
,
90
]. The main treatment
option is the surgical resection of the tumor in combination with radiation therapy and
chemotherapy, and it is most effective when oral cancer is detected early on. The success
of treatments is significantly improved when performed by a multidisciplinary team,
including maxillofacial surgeons, oral pathologists, oncologists, plastic surgeons, dentists,
physiotherapists, radiologists, psychologists, and nutritionists [91].
Plants 2023,12, 2330 7 of 23
Prevention and Antioxidants
To diagnose premalignant lesions in the oral cavity in a timely manner, it is necessary
to make an accurate diagnosis, as these lesions are usually not detected at an early stage.
However, it is essential to identify the risk factors associated with the development of
oral cancer. Preventing and controlling oral cancer is a global challenge; therefore, it is
necessary to establish prevention programs to reduce the incidence of cases [
92
]. Oral
cancer-prevention measures include self-examination, regular visits to the dentist, and
eliminating risk factors. In these prevention programs, it is recommended to include a diet
rich in foods with anti-inflammatory or antioxidant value. Optimal nutritional intake is a
fundamental element for the preservation of health in general. It has been identified that
some foods, such as fruits and vegetables, which are frequently found in the diet can have
this type of protective effect [
93
,
94
]. Reports in recent years have investigated the beneficial
effects of berries with special antioxidant properties in oral cancer [
95
]. In addition, in
recent years, it has been suggested that a diet rich in fruit and vegetable phytochemicals
can help reduce the risk of oral cancer [96,97].
5. Phytochemical Compounds
The phytochemicals or secondary metabolites of plants form a group of compounds
that, although they are not considered essential nutrients, have beneficial properties for
health when they are included in the diet. These compounds provide anti-inflammatory
and antioxidant properties [
15
–
17
,
98
,
99
]. Approximately 10,000 plant-derived compounds
are known in the world; however, only 200 plant species are considered safe for human
consumption [
98
–
100
]. The Western diet, characterized by a high consumption of refined
sugars, saturated fats, and red meat, combined with the inadequate consumption of fruits
and vegetables and other risk factors, is associated with a higher incidence of oral and pha-
ryngeal cancers [
101
]. Therefore, the consumption of phytochemical compounds through
the diet can represent a strategy to reduce the negative effects of cancer risk factors asso-
ciated with oral cancer and can be found in the Ericaceae family, especially in berries [
94
]
(Figures 3and 4).
Plants 2023, 12, x FOR PEER REVIEW 8 of 26
Figure 3. Representative chemical structures of blueberries and cranberries (created with the
MolView program).
5.1. Family Ericaceae
The Ericaceae family is a family of plants composed of at least 4250 species distributed
in 124 genera and nine subfamilies [102]. Within this family is the subfamily Vaccinioidae,
which includes many important blueberry species, such as cranberries (Vaccinium macro-
carpon A.), blueberries (Vaccinium corymbosum L.), European blueberries or bilberries (Vac-
cinium myrtillus L.), among others [103].These fruits contain a high concentration of phy-
tochemical compounds; in particular, blueberries have twice the antioxidant capacity of
red pomegranate [98]. In the last two decades, the therapeutic use of berry-derived com-
pounds in the treatment of cancer has increased due to the association between the devel-
opment of cancer and the consumption of fruits and vegetables [99,100,104]. In the studies
conducted by Greenwald, new approaches have been discovered based on the interac-
tions between the components of the diet, nutrients, genes, and environmental and dietary
factors for the benefit of health [105]. It is important to note that the compounds respon-
sible for biological activity in the Ericaceae family are anthocyanins, flavonoids, anthocya-
nidins, flavanols, flavan-3-ols, proanthocyanidins, phenolic acids, and triterpenoids
[101,102,106–108].
5.2. Anthocyanidins
Anthocyanidins belong to the flavonoid family and anthocyanidins are the largest
group of water-soluble pigments in the plant kingdom. The main sources of these phyto-
chemicals are blueberries, cherries, raspberries, strawberries, etc., which usually give the
characteristic color to this type of fruit [109]. These anthocyanins exhibit a wide range of
biological properties, including antioxidant, anti-inflammatory, antimicrobial, and anti-
tumor activities [110]. The ability of anthocyanins to (1) inhibit cell proliferation, (2) induce
apoptosis by the intrinsic and extrinsic pathways, (3) suppress angiogenesis, (4) suppress
angiogenesis through inhibition, (5) inhibit matrix metalloproteinase (MMP) expression,
and 6) suppress plasminogen activator urokinase has been reported in in vitro and in vivo
studies of hydrogen peroxide and tumor necrosis factor (TNF) induced by the expression
of vascular epidermal growth factor (VEGF) in epidermal keratinocytes [111–116].
5.3. Anthocyanins
The purple, red, and blue colors in vegetables are due to anthocyanins. Fruits, such
as purple cabbage, grapes, and blueberries, are an available food source with this prop-
erty. Anthocyanins are the product of glycosidic replacement in anthocyanidins. Within
the group of anthocyanins are delphinidin, malvidin, petunidin, cyanidin, and peonidin,
together with their fractions of glucose, galactose, and arabinose. These anthocyanins are
found in berries. T hey have bee n reported to present antitumor activity against oral cancer
Figure 3.
Representative chemical structures of blueberries and cranberries (created with the MolView
program).
5.1. Family Ericaceae
The Ericaceae family is a family of plants composed of at least 4250 species distributed
in 124 genera and nine subfamilies [
102
]. Within this family is the subfamily Vaccinioidae,
which includes many important blueberry species, such as cranberries (Vaccinium macro-
carpon A.), blueberries (Vaccinium corymbosum L.), European blueberries or bilberries (Vac-
cinium myrtillus L.), among others [
103
].These fruits contain a high concentration of phyto-
chemical compounds; in particular, blueberries have twice the antioxidant capacity of red
Plants 2023,12, 2330 8 of 23
pomegranate [
98
]. In the last two decades, the therapeutic use of berry-derived compounds
in the treatment of cancer has increased due to the association between the development of
cancer and the consumption of fruits and vegetables [
99
,
100
,
104
]. In the studies conducted
by Greenwald, new approaches have been discovered based on the interactions between
the components of the diet, nutrients, genes, and environmental and dietary factors for the
benefit of health [
105
]. It is important to note that the compounds responsible for biological
activity in the Ericaceae family are anthocyanins, flavonoids, anthocyanidins, flavanols,
flavan-3-ols, proanthocyanidins, phenolic acids, and triterpenoids [101,102,106–108].
5.2. Anthocyanidins
Anthocyanidins belong to the flavonoid family and anthocyanidins are the largest
group of water-soluble pigments in the plant kingdom. The main sources of these phyto-
chemicals are blueberries, cherries, raspberries, strawberries, etc., which usually give the
characteristic color to this type of fruit [
109
]. These anthocyanins exhibit a wide range of
biological properties, including antioxidant, anti-inflammatory, antimicrobial, and antitu-
mor activities [
110
]. The ability of anthocyanins to (1) inhibit cell proliferation, (2) induce
apoptosis by the intrinsic and extrinsic pathways, (3) suppress angiogenesis, (4) suppress
angiogenesis through inhibition, (5) inhibit matrix metalloproteinase (MMP) expression,
and (6) suppress plasminogen activator urokinase has been reported in
in vitro
and
in vivo
studies of hydrogen peroxide and tumor necrosis factor (TNF) induced by the expression
of vascular epidermal growth factor (VEGF) in epidermal keratinocytes [111–116].
5.3. Anthocyanins
The purple, red, and blue colors in vegetables are due to anthocyanins. Fruits, such
as purple cabbage, grapes, and blueberries, are an available food source with this prop-
erty. Anthocyanins are the product of glycosidic replacement in anthocyanidins. Within
the group of anthocyanins are delphinidin, malvidin, petunidin, cyanidin, and peonidin,
together with their fractions of glucose, galactose, and arabinose. These anthocyanins
are found in berries. They have been reported to present antitumor activity against oral
cancer [
99
,
117
–
125
]. The anthocyanins of black rice (Oryza sativa) have anticancer prop-
erties, such as the inhibition of metastasis of the oral cancer cell line (CAL-27), through
the downregulation of matrix metalloproteinases [
126
]. In addition, a similar effect was
observed in other oral cancer cell lines using a lyophilized extract of Rubus idaeus, which
showed a concentration-dependent inhibition of both the migration and invasion of the oral
cancer cell line SCC-9 and SAS [
127
]. Blueberry anthocyanins may induce G2/M cell cycle
arrest in oral cancer cell line KB [
128
]. In addition, anthocyanins also increase the levels of
caspase 9 and cytochrome c in KB cells, which indicates the induction of apoptosis, and
simultaneously increase the amount of p53, which in most neoplasms has lost its function
due to mutation [
128
]. Moreover, certain strawberry-derived anthocyanins, including
cyanidin-3-glucoside (C3G), pelargonidin, and pelargonidin-3-glucoside (P3G), have been
shown to inhibit tumor growth in oral cancer cell lines in the colon and prostate [129].
5.4. Flavan-3-ols and Proanthocyanidins
Flavan-3-ols represent one of the most complex subclasses of flavonoids, which range
from monomers to oligomeric and polymeric proanthocyanidins, also named condensed
tannins [
130
]. In studies on esophageal adenocarcinoma, the antiproliferative effect of
protoanthocyanidins was observed, showing their ability to stop the cell cycle, induce apop-
tosis, or trigger autophagy as an alternative mechanism involving PI3K (phosphoinositide-
3-kinase), AKT (Protein kinase B) and the mammalian target of rapamycin (mTOR) signal-
ing [
131
]. Catechin, epicatechin, and polymeric pro-anthocyanidins are found in cranberries.
It is known that this type of compound can delay the onset of tumors in transgenic mice
that spontaneously develop tumors [20].
Plants 2023,12, 2330 9 of 23
Plants 2023, 12, x FOR PEER REVIEW 9 of 26
[99,117–125]. The anthocyanins of black rice (Oryza sativa) have anticancer properties, such
as the inhibition of metastasis of the oral cancer cell line (CAL-27), through the downreg-
ulation of matrix metalloproteinases [126]. In addition, a similar effect was observed in
other oral cancer cell lines using a lyophilized extract of Rubus idaeus, which showed a
concentration-dependent inhibition of both the migration and invasion of the oral cancer
cell line SCC-9 and SAS [127]. Blueberry anthocyanins may induce G2/M cell cycle arrest
in oral cancer cell line KB [128]. In addition, anthocyanins also increase the levels of
caspase 9 and cytochrome c in KB cells, which indicates the induction of apoptosis, and
simultaneously increase the amount of p53, which in most neoplasms has lost its function
due to mutation [128]. Moreover, certain strawberry-derived anthocyanins, including cy-
anidin-3-glucoside (C3G), pelargonidin, and pelargonidin-3-glucoside (P3G), have been
shown to inhibit tumor growth in oral cancer cell lines in the colon and prostate [129].
5.4. Flavan-3-ols and Proanthocyanidins
Flavan-3-ols represent one of the most complex subclasses of flavonoids, which range
from monomers to oligomeric and polymeric proanthocyanidins, also named condensed
tannins [130]. In studies on esophageal adenocarcinoma, the antiproliferative effect of pro-
toanthocyanidins was observed, showing their ability to stop the cell cycle, induce apop-
tosis, or trigger autophagy as an alternative mechanism involving PI3K (phosphoinosi-
tide-3-kinase), AKT (Protein kinase B) and the mammalian target of rapamycin (mTOR)
signaling [131]. Catechin, epicatechin, and polymeric pro-anthocyanidins are found in
cranberries. It is known that this type of compound can delay the onset of tumors in trans-
genic mice that spontaneously develop tumors [20].
Figure 4. Percentage of some secondary metabolites in blueberries (fresh weight) and cranberries
(dry matter) (A,B) and their anthocyanins (C) and derivatives (D). The percentages are calculated
using the mean between the lowest and highest values identified in the literature for blueberries in
mg/kg of fresh weight and in the case of the lingonberries in mg/100 g of dry matter, as referenced
in the literature
[98,99,132,133]
. The values of each secondary metabolite depend on the size of the
fruit, the state of maturation and, other postharvest conditions.
5.5. Phenolic Acids
Phenolic acids belong to a broad family of phenolic molecules, which are subdivided
into hydroxybenzoic and hydroxycinnamic acids. Each of these compounds has shown
antioxidant, antiproliferative, and anti-inflammatory activities [20]. Cranberries and blue-
berries contain phenolic compounds with antitumor potential [104].
Figure 4.
Percentage of some secondary metabolites in blueberries (fresh weight) and cranberries
(dry matter) (
A
,
B
) and their anthocyanins (
C
) and derivatives (
D
). The percentages are calculated
using the mean between the lowest and highest values identified in the literature for blueberries in
mg/kg of fresh weight and in the case of the lingonberries in mg/100 g of dry matter, as referenced
in the literature [
98
,
99
,
132
,
133
]. The values of each secondary metabolite depend on the size of the
fruit, the state of maturation and, other postharvest conditions.
5.5. Phenolic Acids
Phenolic acids belong to a broad family of phenolic molecules, which are subdivided
into hydroxybenzoic and hydroxycinnamic acids. Each of these compounds has shown
antioxidant, antiproliferative, and anti-inflammatory activities [20]. Cranberries and blue-
berries contain phenolic compounds with antitumor potential [104].
5.6. Triterpenoids
Triterpenes are natural alkenes that are composed of 30 carbon atoms and are made
of six isoprene units. These are usually found in a linear fashion, mainly in the form of
squalene derivatives, tetracyclic and pentacyclic, containing four and five cycles, respec-
tively, as well as those with two or three cycles [
106
,
107
]. In cranberries, ursolic, oleanolic,
and betulinic acids are found in greater proportions [
99
]. These acids have antitumor,
anti-inflammatory and antioxidant activities [
122
]. The compounds responsible for the
biological activity in the Ericaceae family are anthocyanins, flavonoids, anthocyanidins,
flavanols, flavan-3-ols, proanthocyanidins, phenolic acids, and triterpenoids, as shown in
Table 1.
Table 1.
Secondary metabolites present in cranberry and blueberry extracts. * Note 1: dm—dry
matter; fw—fresh weight. Note 2: The concentration of each secondary metabolite depends on the
size of the fruit, the state of maturation, the postharvest conditions, and the environmental and
storage conditions.
Secondary Metabolite Average Concentration in the Extract * Reference:
Vaccinium corymbosum L. (blueberries)
Phenolic acids
Hydroxybenzoic acid 1.5 mg/kg fw [132]
Hydroxycinnamic acid 135 mg/kg fw [132]
Flavonoids [132]
Plants 2023,12, 2330 10 of 23
Table 1. Cont.
Secondary Metabolite Average Concentration in the Extract * Reference:
Flavonols 38.7 mg/kg fw [132]
Anthocyanins 134 mg/kg fw [132]
Vaccinium macrocarpon A. (lingonberries)
Anthocyanins 695–1716 mg/100 g dm [99]
Phenolic acids 327–649 mg/100 g dm [99]
Flavonols 643–1088 mg/100 g dm [99]
Flavan-3-ols and proanthocyanidins 860–1283 mg/100 g dm [99]
Triterpenoids 2528–3201.5 mg/kg dm [99]
6. Berries and Cancer
Berries are rich in minerals, vitamins, fatty acids, fiber, and polyphenolic compounds,
including pterostilbene, malvidin, and malvidin-3-galactosidase [
20
,
130
]. Cranberries and
blueberries have been shown to have antitumor properties
in vitro
,
in vivo
, and in clinical
studies [
117
–
119
]. This activity is due to the presence of compounds, such as phenolic acids,
flavonoids, anthocyanins, procyanidins, ascorbic acid, quercetin, kaempferol, catechin,
epicatechin, p-coumaric acid, gallic acid, caffeic acid, ferulic acid, hydroxycinnamic acid,
and chlorogenic acid, which are able to inhibit proinflammatory molecules, decrease
oxidative stress, prevent DNA damage, inhibit tumor cell proliferation, and enhance tumor
cell apoptosis Table 2[
120
,
121
]. Chlorogenic acid, which is found in a variety of fruits,
including blueberries, has been studied for its potential health benefits, particularly for
its antioxidant and potential antitumor properties. The effects of coffee consumption on
antitumor activity are complex and multifaceted. This is because coffee contains a variety
of compounds that have been studied for their potential health effects [
134
]. Despite its
high antioxidant content, the processing and heating of coffee may reduce its antitumor
activity [
135
]. Further investigations are needed to understand the specific mechanisms by
which coffee exerts its potential antitumor effects. Seeram determined that the polyphenolic
compounds present in cranberry were responsible for the antiproliferative effects found
in oral, prostate, and colon cancer cells, not the sugars [
118
]. These findings have been
extended to other widely consumed berries. These include blackberries, black raspberries,
blueberries, red raspberries, and strawberries [
119
]. Protoanthocyanidins derived from V.
macrocarpon were reported to be the relevant bioactives involved in the reduction in urinary
tract infections after cranberry juice consumption due to the inhibition of the adhesion of
E. coli fimbriae to uroepithelial cells [
136
]. Furthermore, when these protoanthocyanidins
were used in tumor explants of colon or prostate cancer cells, a decrease in the growth rate
was observed
in vivo
[
137
]. Therefore, it is important to apply this knowledge to models of
oral cancer and to strengthen epidemiological studies that assess the benefit of berries to
reduce the incidence of oral cancer.
6.1. Mechanism of Action of Berries in Cancer
The mechanism of action of berry-derived phytochemicals can induce various ef-
fects on tumor cells, such as the inhibition of the nuclear transcription factor (NF-
κ
B),
inhibition of the MAP kinase pathway, interference with the production of detoxification
enzymes, interference with the beta-catenin modulation of apoptosis, and modulation of
the PI3K/AKT/mTOR pathway [
138
,
139
]. Studies have reported that polyphenols have
an action on the NF-
κ
B pathway, with effects on the Mitogen-activated protein kinase
(MAP kinase pathway), the cAMP-dependent protein kinase (PKA) pathway, apopto-
sis, and the generation of oxidative stress, processes that depend on the consumption of
berries in the diet [
139
,
140
]. The physicochemical and biotransformation properties of
berry polyphenols by liver enzymes and the intestinal microbiota exert different effects
on tumor cells in
in vitro
and animal models [
141
,
142
]. Resveratrol is the most widely
characterized example of polyphenols regarding its cellular effects. This compound, found
in red grapes, can have effects on tumor cells, in addition to inducing cell cycle arrest
Plants 2023,12, 2330 11 of 23
in oral cancer lines, and it can induce DNA damage and increase cell death in several
cancer models [
143
,
144
]. Resveratrol appears to influence autophagy, as an alternative
mechanism, and apoptosis, affecting oral cancer cell resistance to cisplatin through the
AMPK and PI3K/AKT/mTOR pathways [
145
,
146
]. In esophageal adenocarcinoma, the
anti-proliferative effects of resveratrol proanthocyanidins were observed, in addition to
their ability to arrest the cell cycle [
147
]. Blackberries have also been reported to inhibit
oxidative stress in rat esophageal squamous cell carcinogenesis models and the hydrogen
peroxide-activated NF-kB/MAPK pathway [
148
]. In a study, a potential mechanism of oral
cancer inhibition was identified through black raspberries via the glycolysis and AMPK
pathways [
149
]. The authors suggested administering blackberries to animals to prevent
oral cancer. Black raspberry phytochemicals can negatively modulate these pathways and
thus compromise tumor cell growth (Figure 5) [
149
]. Berry flavonoids and polyphenols
have been associated with effects on inflammation, apoptosis, autophagy, and the inhibition
of the PI3K/Akt/mTOR pathway, among others, in cancer models [
149
]. The effects on the
immune system of berries have shown effects on cancer metabolism in mice against the
cell cycle, activation of MAP kinase signaling, DNA repair, leukocyte extravasation, and
modulation of the inflammatory response [150].
Plants 2023, 12, x FOR PEER REVIEW 12 of 26
Figure 5. Mechanism of action of berries in cancer. Created with BioRender.com (accessed on 10
March 2022)
6.2. Mechanism of Action of Berry-Derived Phytochemicals in Oral Cancer
The fruits of the species Vaccinium ssp. represent an excellent natural food resource
rich in phenolic compounds, flavonoids, polyphenols, anthocyanins, procyanidins,
chlorogenic acid, ascorbic acid, quercetin, kaempferol, catechin, epicatechin, p-coumaric
acid, gallic acid, caffeic acid, ferulic acid, and hydroxycinnamic acid, among others [110].
The consumption of both fresh and processed products can be an alternative to prevent
oral squamous cell cancer [151].
6.3. Consumption of Cranberries and Blueberries in Protection against Risk Factors for Oral
Cancer
Preventive measures to protect against oral cancer are classified into three categories:
primary, secondary, and tertiary [152]. Among these measures is chemoprevention, which
consists of the administration of an agent to prevent the appearance of cancer [153]. These
agents can be drugs or natural products that are easy to administer, with little or low
toxicity, and that do not cause long-term sequelae. Blueberries are interesting candidates
because they contain many phytochemicals with antitumor potential [154]. These phyto-
chemicals can be effective in the short and long terms, and they can be consumed fresh or
processed. The main source of phytochemicals in cranberries and blueberries is anthocy-
anins, which account for more than 60% of the total polyphenols in their ripe state. This
means approximately 387–487 mg/100 g anthocyanins in their fresh form [155]. To take
advantage of these effects, it is recommended to drink a 250 mL cup of fresh cranberry or
processed juices daily for at least 28–36 days, both in the morning and afternoon [156–
159]. However, it is important to note that the processed juice should not contain ascorbic
acid, as it reduces the number of phenolic compounds present in the juice and its biologi-
cal efficacy by up to 10% [160]. Cranberries and blueberries are rich in phytochemicals
with anticancer potential, such as anthocyanins and flavanols [161]. These phytochemicals
can be consumed both fresh and processed to exert their potential long-term protective
effects against oral cancer. Other important components in blueberries, especially cran-
berries, are flavan-3-ol and triterpenoids. These phytochemicals can also contribute to the
treatment of oral premalignant lesions and the reduction in other factors that promote oral
carcinogenesis. It is important to mention that the effects of climate change on secondary
metabolism cover many aspects, ranging from the molecular level to the overall effects on
organisms resulting from changing concentrations of phytochemical compounds. To ob-
tain the essential information needed to understand how plants perform under changing
climatic conditions, a thorough analysis of the existing knowledge on the effects of climate
Figure 5.
Mechanism of action of berries in cancer. Created with BioRender.com (accessed on 10
March 2022).
6.2. Mechanism of Action of Berry-Derived Phytochemicals in Oral Cancer
The fruits of the species Vaccinium ssp. represent an excellent natural food resource rich
in phenolic compounds, flavonoids, polyphenols, anthocyanins, procyanidins, chlorogenic
acid, ascorbic acid, quercetin, kaempferol, catechin, epicatechin, p-coumaric acid, gallic acid,
caffeic acid, ferulic acid, and hydroxycinnamic acid, among others [
110
]. The consumption
of both fresh and processed products can be an alternative to prevent oral squamous cell
cancer [151].
6.3. Consumption of Cranberries and Blueberries in Protection against Risk Factors for Oral Cancer
Preventive measures to protect against oral cancer are classified into three categories:
primary, secondary, and tertiary [
152
]. Among these measures is chemoprevention, which
consists of the administration of an agent to prevent the appearance of cancer [
153
]. These
agents can be drugs or natural products that are easy to administer, with little or low
toxicity, and that do not cause long-term sequelae. Blueberries are interesting candidates
because they contain many phytochemicals with antitumor potential [
154
]. These phyto-
chemicals can be effective in the short and long terms, and they can be consumed fresh
or processed. The main source of phytochemicals in cranberries and blueberries is antho-
cyanins, which account for more than 60% of the total polyphenols in their ripe state. This
Plants 2023,12, 2330 12 of 23
means approximately 387–487 mg/100 g anthocyanins in their fresh form [
155
]. To take
advantage of these effects, it is recommended to drink a 250 mL cup of fresh cranberry or
processed juices daily for at least 28–36 days, both in the morning and afternoon [
156
–
159
].
However, it is important to note that the processed juice should not contain ascorbic acid,
as it reduces the number of phenolic compounds present in the juice and its biological
efficacy by up to 10% [
160
]. Cranberries and blueberries are rich in phytochemicals with
anticancer potential, such as anthocyanins and flavanols [
161
]. These phytochemicals can
be consumed both fresh and processed to exert their potential long-term protective effects
against oral cancer. Other important components in blueberries, especially cranberries,
are flavan-3-ol and triterpenoids. These phytochemicals can also contribute to the treat-
ment of oral premalignant lesions and the reduction in other factors that promote oral
carcinogenesis. It is important to mention that the effects of climate change on secondary
metabolism cover many aspects, ranging from the molecular level to the overall effects
on organisms resulting from changing concentrations of phytochemical compounds. To
obtain the essential information needed to understand how plants perform under changing
climatic conditions, a thorough analysis of the existing knowledge on the effects of climate
change components on berry secondary metabolites is crucial. Further research is needed to
better understand the complex effects of multiple environmental factors on berry secondary
metabolites [
162
]. However, there are still a relatively small number of studies investigating
the metabolome in berries. Berries, as a group of fruits, have remarkable resilience in the
preservation of their inherent qualities. Cranberries are widely recognized for their ability
to retain their distinctive biochemical characteristics [163].
6.3.1. Cranberries and Blueberries and Their Protection against Tobacco-Induced Oral Cancer
A variety of oral lesions, including leukoplakia, erythroplakia, oral submucosal fi-
brosis, and oral cancer, have been implicated in tobacco use [
164
]. This is due to the
presence of over sixty carcinogens in the smoke of cigarettes, as well as, at minimum,
sixteen in uncombusted tobacco [
91
]. This includes tobacco-specific nitrosamines, such as
4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK) and N’-nitrosonornicotine (NNN);
polycyclic aromatic hydrocarbons, such as benzo[
α
] pyrene; and aromatic amines, such as
4-aminobiphenyl, which have been shown to cause cancer [
165
]. Strategies to use chemo-
preventive agents to counteract or inhibit the effects of tobacco use on oral carcinogenesis
can be very useful in preventing this disease. One example of these agents is blueberry
extracts, which have been shown in an
in vivo
study to inhibit the initiation and progres-
sion of carcinomas through the inhibition of the TGF-
β
and PI3K/AKT pathways [
166
,
167
].
Furthermore, supplementation suppressed the activation of NF-
κ
B, preventing the translo-
cation of this transcription factor [
168
]. Furthermore, these extracts have been shown
to modulate the expression of oncomiR miR-21 and the tumor suppressor let-7 [
167
]. A
study on a mouse model showed that black raspberry extracts inhibit the binding of the
carcinogen dibenzo [
α
, l] pyrene-DNA, which is crucial for the repair of lesions caused
by this carcinogen in DNA [
169
]. Protocatechuic acid, found in blueberries, has also been
shown to be responsible for some of the benefits of anthocyanin consumption, including
the inhibition of mutagenic effects as well as the generation of DNA adducts of the tobacco
smoke carcinogen dibenzopyrene [94].
6.3.2. Cranberries and Blueberries and Their Protection against Alcohol-Induced Oral Cancer
Alcohol consumption, such as tobacco smoking, has been recognized as an important
contributor to the development of oral cancer for over fifty years. It has been associated
with approximately 75% of cancers affecting the superior aerodigestive tract and causes
changes in the cellular structure of the oral epithelium [
170
]. Mechanisms through which
the consumption of alcohol causes carcinogenic damage are not fully understood; however,
they may include the genotoxic effect of acetaldehyde on the oral mucosa, an increase in
the concentration of estrogens, the role of a solvent producing other carcinogens, such as
those from tobacco, the generation of ROS and nitric oxide synthases (NOS), and alterations
Plants 2023,12, 2330 13 of 23
in folate metabolism [
171
]. It is believed that the consumption of blueberries may have
chemopreventive effects on oral cancer induced by alcohol consumption due to its content
of phytochemicals, such as quercetin and resveratrol [
172
]. Anthocyanins, which are
one of the major components of blueberries, have interesting anticancer properties that
are useful for the prevention of oral cancer [
116
]. One of these compounds, malvidin
(malvidin-3-glucoside), showed inhibitory activity against (Signal transducer and activator
of transcription 3) STAT-3 within the oral cancer cell line (SCC131) by suppressing the
phosphorylation and nuclear translocation of this factor, which resulted in cell cycle arrest
and mitochondrial-mediated apoptosis [
120
]. In addition, blueberry extract has been shown
to inhibit The Janus-Kinase signal transducer and the transcription activation pathway
(JAK/STAT-3) signaling by modulating the downstream sites affecting cell proliferation
and apoptosis in a hamster model of oral oncogenesis [
120
]. Therefore, due to the action
of this phytochemical, it is possible to inhibit oral carcinogenesis by alcohol, which is an
important inducing factor of this type of cancer that can contribute to the large number
of people who regularly consume this substance [
173
,
174
]. Other studies have shown the
chemopreventive capacity of grape wine in cells of the oral mucosa. Although regular
consumption in moderate doses produces metabolites, such as acetaldehyde, which is
the main producer of DNA adducts, it has been shown that grape wine has the ability
to mitigate the deleterious actions of alcohol and reduce the chances of developing oral
cancer [
124
,
175
]. This is due to the presence of phenolic compounds, such as those found
in cranberries, which activate the p53 tumor suppressor gene to induce cell cycle arrest as
well as apoptosis in cells of the oral cavity [119].
6.4. Consumption of Cranberries and Blueberries Protects against the Effects of Bacteria and Poor
Oral Hygiene
The oral cavity is a special place where there are more than 250 varieties of microor-
ganisms called commensals, which have a crucial role in maintaining the individual status
of organisms [
176
]. Many of these species, according to epidemiological studies, are closely
related to oral cancer. Among the most important are Fusobacterium nucleatum and Porphy-
romonas gingivalis, among others, which have been related to different types of carcinomas
and oral tumor processes [
177
]. Additionally, some papillomaviruses, oral fungi, such
as Candida albicans, and parasites have been linked to oropharyngeal cancer [
178
]. Can-
dida albicans infection has been implicated in the initiation and progression of oral cancer
through the activation of proto-oncogenes, induction of DNA damage, and overexpres-
sion of oncogenic pathways [
179
]. Inflammatory signaling in the oral mucosa can also be
modulated by the phytochemicals of blueberries, especially red berries. The crude extracts
and their fractions enriched with other species of red fruits (Vaccinium myrtillus L. and
Malpighia punicifolica L.) exert antiadhesion activity against Candida spp. when used at
concentrations > 1.25 mg/mL [
180
]. This mechanism is related to the action of type-A
cranberry proanthocyanidins, which do not have a relevant effect on Candida spp. but do so
on the adhesion of this on the oral mucosa [
181
,
182
]. Thus, for carcinogenic implantation
functions to occur, phenomena, such as microbial dysbiosis, colonization, and translocation,
must occur, which produce an excessive inflammatory response, host immunosuppres-
sion, enhancement of malignant transformation, anti-apoptotic effects, and the secretion
of carcinogens [
178
]. Therefore, the consumption of blueberries and cranberries may be a
potential source to prevent these types of infections [
183
]. An example of this is the effect
of proanthocyanidins (PACs) in both blueberries and cranberries to reduce the deleterious
effects of the Porphyromonas gingivalis species on the cells of the oral mucosa [
184
]. This is
achieved by protecting against the damage produced by said bacteria in the keratinocytic
gingival barrier, inhibiting its translocation, reducing the proteolytic degradation of tight
epithelial junctions, and reducing the secretion of IL-6 and IL-8, among others, in an
in vitro
model of the gingival keratinocyte barrier against P. gingivalis [
185
]. In addition, PACs from
cranberries have also been associated with antimicrobial, anti-adhesion, antioxidant, and
anti-inflammatory properties, which is why they can be potentially useful in the prevention
Plants 2023,12, 2330 14 of 23
of periodontal disease that affects dental tissues [
186
]. This is achieved through the inhibi-
tion of both bacterial and host-derived proteolytic enzymes, as well as host inflammation
and osteoclast differentiation and activity [186].
6.5. Cranberries and Blueberries and Their Protection against Oral Cancer Induced by Viral Infections
Two infectious factors associated with the onset and development of oral cancer are
human papillomavirus (HPV) and Epstein–Barr virus (EBV) [
187
,
188
]. For example, the
polyphenolic and flavonoid components (also found in cranberries and blueberries) in
the Polygonatum odoratum plant have been shown in recent studies to have antibacterial,
antifungal, antioxidant, anti-inflammatory, and anticancer activities. A study has shown
that extracts of this plant significantly affect human lymphoblastoid carriers of the Epstein–
Barr virus genome through the induction of apoptosis, cell cycle arrest, inhibition of cell
proliferation, migration, and colonization [
189
]. Moreover, this extract suppresses proteins
that are essential to cell proliferation, colonization, and migration, including cyclin D,
cyclooxygenase 2 (COX-2), matrix metalloproteinase-9 (MMP-9), and vascular endothelial
growth factor A (VEGF-A) [
188
]. This makes these components of interest in the prevention
of oral cancer mediated by this virus.
Table 2. Effects of cranberry extracts and phytochemicals against oral cancer.
Cranberry Type
Type of Study Conducted
(In Vitro/In Vivo/
Clinical Study)
Evidence against Oral Cancer Reference
Vaccinium corymbosum L.
(blueberries) In vitro
The methanolic extract of blueberries inhibits cell
proliferation in the oral cancer line KB. [128,188]
In vivo/In vitro
Dietary administration of blueberry produces
significant effects on the SCC131 cancer cell line
through the inhibition of TGF-βand NF-κB, as
well as act against invasion and angiogenesis at
doses higher than 200 mg/kg.
[20,167]
In vitro
The phytochemical pterostilbene present in
blueberries induces apoptotic cell death and,
through autophagy in cisplatin-resistant human
oral cancer cells (CAR cells), which is related to
the AKT pathway, are mediated by the
suppression of MDR1.
[100]
Vaccinium macrocarpon A.
(lingonberries) In vitro The methanol extract of the cranberries inhibits
cellular proliferation in the line of oral cancer KB.
[128,188]
In vivo/In vitro
The extract composed of proanthocyanidins
(C-PAC) derived from cranberries inhibits the
growth of resistant and acid-sensitive
esophageal adenocarcinoma (EAC) cells, both in
cell lines and xenotransplant mice, inducing
caspase-independent cell death, mainly by the
autophagic pathway.
[131]
In vitro
The hydroethanolic extract of cranberries
produces an antiproliferative effect on the
caspase-independent KB cell line, mainly by the
autophagic route.
[190]
In vitro
Cranberry extract produces an inhibitory effect
on the proliferation of OSCC lines cAL27 and
SCC25 at an optimal concentration of 40
µ
g/mL,
producing the upstream regulation of caspases 2
and 8, and effects cell adhesion, cell morphology,
and the cell cycle.
[191]
Plants 2023,12, 2330 15 of 23
7. Limitations and Perspectives of the Consumption of Cranberries and Blueberries for
Protection against Oral Cancer
Diet is a complex issue influenced by cultural and resource-related factors. Scientific
research aimed at understanding the molecular mechanisms underlying the reduced risk
of cancer associated with certain dietary habits has revealed that isolating individual com-
pounds fails to capture the broad range of benefits observed in epidemiological studies.
Allium vegetables, including garlic, onions, chives, shallots, and leeks, present an intrigu-
ing case. This diverse group of plants comprises over 500 species and contains numerous
bioactive compounds, particularly sulfur compounds, such as allicin, S-allylcysteine, di-
allysulfides, and others. Assessing the impact of allium consumption remains challenging
due to the likely influence of various environmental and dietary variables on its potential
cancer-preventive effects. However, several phytochemicals found in allium vegetables
have demonstrated their ability to reduce cancer risk at different stages of cancer develop-
ment, including initiation, promotion, and progression. Similar findings have also been
observed in the context of berries and fruits. The scientific evidence supports the notion that
lifestyle modifications, particularly dietary changes, can enhance cancer-prevention efforts.
However, it is important to avoid overstating the significance of individual components,
and further studies are warranted to expand our understanding [192].
Limitations
Oral cancer is a multifaceted disease involving various factors that trigger the carcino-
genic process. Strategies incorporating antioxidants and phytochemicals from cranberries
can help prevent these factors by modifying molecular mechanisms and inducing apoptosis
in tumor cells. However, it is crucial to consider the source of blueberries (natural or
processed) as the latter may degrade phytochemicals, reducing their protective effects.
Furthermore, there is a lack of clinical research investigating the impact of cranberries
and blueberries on oral cancer through traditional consumption methods (juice and fresh)
among smokers and regular alcohol consumers to determine their protective effects. The ef-
fectiveness of cranberry supplementation also depends on the stage of carcinogenesis, with
varying benefits depending on tumor development levels. Despite the existing evidence,
scientific studies supporting the use of these fruits for oral cancer prevention and treatment
are limited. Additional research is needed to recommend their consumption, particularly
in advanced stages of oral tumor diseases, such as metastasis, where the effects remain
unknown. Blueberries contain phytochemicals, such as anthocyanins, quercetin, and ellagic
acid, which similarly reduce the diet-related risk factors associated with oral cancer, akin
to black raspberries. It is important to be aware of these limitations in the interpretation
of the available published scientific evidence on the association between berries and oral
cancer reduction.
Perspectives: conducting rigorous clinical trials with carefully designed protocols
and representative samples is a promising approach to berry research for reducing oral
cancer risk factors. To develop precise treatment strategies, it is critical to understand the
specific mechanisms by which the bioactive compounds in berries exert their beneficial
effects. In addition, there is great promise for increasing efficacy and improving outcomes
by exploring combinations of berries with other treatments. Elucidating the mechanisms of
action and exploring berry combinations with other treatments to improve outcomes are
future perspectives in this field.
8. Conclusions
Studies performed
in vitro
,
in vivo
, and in clinical research have shown that the phyto-
chemicals and polyphenolic compounds found in blueberries, cranberries, and other berries
have antitumor properties. Polyphenolic compounds found in cranberries are responsible
for the antiproliferative effects on oral cancer cells in
in vitro
and
in vivo
models. Berries’
mechanisms of action in oral cancer include: (i) the inhibition of inflammation through
interference with the nuclear transcription factor NF-
κ
B, (ii) effects on proliferation by
Plants 2023,12, 2330 16 of 23
interfering with the MAP kinase pathway, (iii) reduction in resistance by interfering with
the expression of detoxification enzymes, (iv) interference with the
β
-catenin signaling
pathway, (v) modulation of apoptosis, and (vi) modulation of the antiapoptotic and an-
abolic pathways of PI3K/AKT/mTOR. The use of protective strategies is based on the
consumption of functional foods, nutraceuticals, or supplements based on fruits, such as
berries of the species Vaccinium ssp. It can be of great interest to reduce the effects of the
risk factors associated with oral cancer.
Author Contributions:
Conceptualization, C.E.-C., M.A.B.-C. and A.Z.-D.; investigation, M.E.-L.,
A.L.-M., D.M.-S., F.H.-S., D.C.-R., B.R.Y.-O. and J.L.V.-G.; writing—original draft preparation, S.M.-F.,
L.A.G.-C., F.H.-S., A.L.-M., D.M.-S. writing—review and editing, H.L.-E., J.L.V.-G. and C.P.M.-V.;
visualization, A.Z.-D. and J.L.V.-G. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
OSCC Oral squamous carcinoma cell
HPV Human papillomavirus
EBV Epstein–Barr virus
NNN N0-nitrosonornicotine
NNK 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone
ROS Reactive oxygen species
BMI Body mass index
EGFR/c-erb Epidermal growth factor receptor
TNF tumor necrosis factor
MMP matrix metalloproteinase
CAL-27 oral cancer cell line
C3G cyanidin-3-glucoside
PACs Proanthocyanidins
COX-2 Cyclooxygenase 2
MMP-9 Matrix metalloproteinase-9
VEGF-A Vascular endothelial growth factor A
NF-κB Nuclear transcription factor
NOSs Nitric oxide synthases
P3G pelargonidin-3-glucoside
SCC131 oral cancer cell line 131
PI3K phosphoinositide-3-kinase
AKT Protein kinase B
mTOR the mammalian target of rapamycin
MAP Mitogen-activated protein kinase
PKA cAMP-dependent protein kinaseB
AMPK the AMP-activated protein kinase
TGF-βTransforming growth factor-β
STAT-3 Signal transducer and activator of transcription 3
JAK/STAT The Janus-Kinase signal transducer and the transcription activation pathway
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