Onco-Preventive and Chemo-Protective Effects of Apple Bioactive Compounds

Abstract

Cancer is one of the leading causes of death globally. Epidemiological studies have strongly linked a diet high in fruits to a lower incidence of cancer. Furthermore, extensive research shows that secondary plant metabolites known as phytochemicals, which are commonly found in fruits, have onco-preventive and chemo-protective effects. Apple is a commonly consumed fruit worldwide that is available all year round and is a rich source of phytochemicals. In this review, we summarize the association of apple consumption with cancer incidence based on findings from epidemiological and cohort studies. We further provide a comprehensive review of the main phytochemical patterns observed in apples and their bioavailability after consumption. Finally, we report on the latest findings from in vitro and in vivo studies highlighting some of the key molecular mechanisms targeted by apple phytochemicals in relation to inhibiting multiple ‘hallmarks of cancer’ that are important in the progression of cancer.

Full text

nutrients
Review
Onco-Preventive and Chemo-Protective Effects of Apple
Bioactive Compounds
Linda Nezbedova 1,2 , Tony McGhie 3, Mark Christensen 4, Julian Heyes 1, † , Noha Ahmed Nasef 2, †
and Sunali Mehta 5, 6,*,†


Citation: Nezbedova, L.; McGhie, T.;
Christen-sen, M.; Heyes, J.; Nasef,
N.A.; Mehta, S. Onco-Preventive and
Chemo-Protective Effects of Apple
Bioactive Compounds. Nutrients 2021,
13, 4025. https://doi.org/10.3390/
nu13114025
Received: 21 September 2021
Accepted: 3 November 2021
Published: 11 November 2021
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Copyright: © 2021 by the authors.
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This article is an open access article
distributed under the terms and
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Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
1School of Food and Advanced Technology, Massey University, Palmerston North 4442, New Zealand;
l.nezbedova1@massey.ac.nz (L.N.); j.a.heyes@massey.ac.nz (J.H.)
2Riddet Institute, Massey University, Palmerston North 4442, New Zealand; n.nasef@massey.ac.nz
3The New Zealand Institute for Plant and Food Research Limited, Palmerston North 4442, New Zealand;
tony.mcghie@plantandfood.co.nz
4Heritage Food Crops Research Trust, Whanganui 4501, New Zealand; mark@heritagefoodcrops.co.nz
5Pathology Department, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand
6Maurice Wilkins Centre for Biodiscovery, University of Otago, Dunedin 9054, New Zealand
*Correspondence: sunali.mehta@otago.ac.nz; Tel.: +64-3-479-7285
† These authors contribute equally to this work.
Abstract:
Cancer is one of the leading causes of death globally. Epidemiological studies have strongly
linked a diet high in fruits to a lower incidence of cancer. Furthermore, extensive research shows
that secondary plant metabolites known as phytochemicals, which are commonly found in fruits,
have onco-preventive and chemo-protective effects. Apple is a commonly consumed fruit worldwide
that is available all year round and is a rich source of phytochemicals. In this review, we summarize
the association of apple consumption with cancer incidence based on findings from epidemiological
and cohort studies. We further provide a comprehensive review of the main phytochemical patterns
observed in apples and their bioavailability after consumption. Finally, we report on the latest
findings from
in vitro
and
in vivo
studies highlighting some of the key molecular mechanisms
targeted by apple phytochemicals in relation to inhibiting multiple ‘hallmarks of cancer’ that are
important in the progression of cancer.
Keywords:
fruit;apple; phytochemicals; cancer; chemoprevention; antioxidants; phenolics;triterpenoids
1. Introduction
Chronic diseases including cancer continue to remain a public health burden glob-
ally [
1
–
5
]. In 2020, cancer was the second leading chronic illness following cardiovascular
disease, with an estimate of 19 million new cases and accounting for 10 million deaths per
year, globally [
6
,
7
]. Data from GLOBOCAN [
7
] show that cancers of the breast are the most
commonly diagnosed followed by cancers of the lung, colorectal, and prostate.
To reduce cancer’s global health burden, it is necessary to promote both cancer treat-
ment and cancer prevention. There is growing evidence that phytochemicals found in
vegetables and fruits play a major role in cancer aetiology. Furthermore, diet and simple
dietary changes incorporating fruits and vegetables can influence the risk of cancer [
8
].
Apples are an example of commonly available fruits worldwide that are a rich source of
phytochemicals. There is a milieu of studies around the health benefits of apples includ-
ing onco-preventive effects. However, translating this information into an appropriate
intervention requires understanding of how the different components of apples contribute
to their health benefit. These components include differences in the phytochemical con-
centration within the skin vs. flesh of the apple, the impact of the apple food matrix, and
absorption and bioavailability of apple phytochemicals. In this review, we provide detailed
insight into selected dietary phytochemicals found in apples, their onco-protective role
in cancer, and their effect on different pathways implicated in cancer development and
Nutrients 2021,13, 4025. https://doi.org/10.3390/nu13114025 https://www.mdpi.com/journal/nutrients

Nutrients 2021,13, 4025 2 of 29
progression. This review collates details from different studies related to apples and apple
phytochemicals in order to provide a more holistic understanding around the effects of
apple consumption on cancer. We also highlight the gaps in the literature to promote more
relevant studies in this field including clinical trials.
2. Cancer
Cancer is a group of heterogeneous diseases that can occur in multiple parts of the
body [
9
]. Triggers for cancer are complex and include genetic predispositions, environment,
and lifestyle [
10
,
11
]. In this section, we briefly describe the different steps involved in cancer
development (carcinogenesis) to better understand the pathways targeted by different
phytochemicals described in subsequent sections of this review.
Carcinogenesis is a multi-step process involving initiation, promotion, and progres-
sion of cancer [
12
–
14
]. Initiation is the first irreversible step of carcinogenesis and refers to
the genetic and epigenetic alterations in somatic cells mainly involving proto-oncogenes
such as RAS, c-Myc, and tumor suppressor genes such as Rb and p53 [
15
–
19
]. Promotion
is the second phase of carcinogenesis where non-mutagenic promoting agents result in
reversible changes in the genome, giving cells the ability to proliferate uncontrollably and
expand [
14
,
20
]. Growth factors such as epidermal growth factors (EGF), hormones includ-
ing estrogen, and external factors such as chemical compounds from diet are examples of
agents promoting these non-mutagenic events within the cell [
21
,
22
]. Progression repre-
sents a later stage of tumor development and is characterized by accumulation of multiple
genetic changes, including increased mutational load, number, and arrangement of chromo-
somes and epigenetic changes [
23
]. Continuous accumulation of genomic changes within
the cells allows them to acquire multiple ‘hallmarks of cancer’ including uncontrolled
growth, ability to resist cell death, alter metabolism, evade the immune system, and invade
and spread to other tissues and organs (reviewed in detail [24]).
3. Importance of Phytochemicals from Diet in Management of Cancer
Diet can influence cancer development in both positive and negative ways. It is
estimated that a healthy lifestyle and healthy dietary practices could help lower incidence
of all cancers by 30-40% [
25
]. Furthermore, a diet rich in vegetables, fruits, whole grains,
dietary fiber, omega-3 fatty acids, and certain micronutrients (e.g., vitamins and calcium)
protects against some cancers [
26
–
28
]. In contrast, diets rich in meat, processed foods, fried
foods, and smoked foods can increase the risk of developing some cancers [29–31].
For a healthy diet, the World Health Organization (WHO) recommends the consump-
tion of a minimum of five portions or 400 g of fruit and vegetables per day, of which two
portions should constitute fruit [
32
,
33
]. Studies have shown differences in fruit consump-
tion across the world based on the socioeconomic status, sex, and geographic location.
From these studies, cancer incidence was estimated to decrease by 14% with consumption
of 550–600 g of fruit and vegetable per day, which is greater than the current recommenda-
tions made by WHO [
34
,
35
]. These results suggest that a healthy diet such as one high in
fruits and vegetables has protective effects against different types of cancer.
Protective effects of fruit against cancer are related to their high content of bioactive
compounds (phytochemicals). Phytochemicals are secondary metabolites from plants
responsible for the taste, color, and aroma of fruit. Research suggests that phytochemicals
are beneficial in preventing and treating oxidative damage and inflammation, which are
important risk factors in cancer development [
36
–
39
]. Moreover, phytochemicals have
significant onco-preventive and chemo-protective effects, and this has been reviewed
extensively elsewhere [38,40–45].
One fruit that is a rich and important source of bioactive phytochemicals in Western
diets is the apple [
46
–
49
]. Apples are globally consumed due to their year-round availability,
their cultivar diversity, low price, and easy storage [
46
,
50
]. The subsequent sections of this
review will focus specifically on the onco-preventive and chemo-protective properties of
phytochemicals found in apples.

Nutrients 2021,13, 4025 3 of 29
4. Apple Phytochemical Profile and Bioavailability
To better understand the health benefits of apples, in this section we provide a compre-
hensive review of the main phytochemical patterns observed in apples and their potential
health benefits depending on variety and the consumed part of the fruit (skin/peel versus
the flesh of the apple).
Apples contain a wide variety of phytochemicals, including triterpenoids, organic
acids, fatty acids, and apple phenolic compounds (Figure 1) [
51
]. Triterpenoids are compo-
nents mainly of apple waxes [
52
]. The main triterpenoids found in apples are oleanolic,
betulinic, and ursolic acid and their derivatives such as maslinic, corosolic, euscaphic,
pomaceic, and pomolic acids [53].
Nutrients 2021, 13, x FOR PEER REVIEW 3 of 28
of this review will focus specifically on the onco-preventive and chemo-protective prop-
erties of phytochemicals found in apples.
4. Apple Phytochemical Profile and Bioavailability
To better understand the health benefits of apples, in this section we provide a com-
prehensive review of the main phytochemical patterns observed in apples and their po-
tential health benefits depending on variety and the consumed part of the fruit (skin/peel
versus the flesh of the apple).
Apples contain a wide variety of phytochemicals, including triterpenoids, organic
acids, fatty acids, and apple phenolic compounds (Figure 1) [51]. Triterpenoids are com-
ponents mainly of apple waxes [52]. The main triterpenoids found in apples are oleanolic,
betulinic, and ursolic acid and their derivatives such as maslinic, corosolic, euscaphic,
pomaceic, and pomolic acids [53].
Figure 1. Schematic showing the classification of phytochemicals present in apple.
The most well-studied group of apple phytochemicals for their health benefits are
phenolic compounds [54]. Studies show that apples are an important source of phenolic
compounds in our diet contributing to 22% of phenolic intake [55,56]. Most of the phenolic
compounds in the fruit are usually present in the conjugated form such as glycosides or
esterified carboxylic acids. However, compared to other fruit, apples contain more of the
readily bioavailable free forms of phenolic compounds [57–59]. For instance, the ‘Red De-
licious’ apple had the highest level of free forms of phenolic compounds compared to
pear, plum, kiwifruit, and peach [60].
Phenolic compounds in apple can be sub-divided into two main groups (Table 1,
Figure 1) known as flavonoids and phenolic acids. Flavonoids can be further divided into
four structural subclasses including anthocyanidins, flavonols, dihydrochalcones, and fla-
van-3-ols (flavanols) which can exist in the monomeric and oligomeric form [49,61] (Table
1). Phenolic acids include chlorogenic acid, hydroxycinnamic acid, and hydroxybenzoic
acid [49,61]. In general, chlorogenic acid and monomeric and polymeric flavanols are the
major phenolic compounds, whereas anthocyanins and dihydrochalcones are minor phe-
nolic compounds of apples [62]. Moreover, anthocyanidins are responsible for the apple
redness [63,64]. Therefore, anthocyanidins are abundant in the apple cultivars with red
skin (e.g., ‘Red Delicious’) and are either present in low concentrations or absent in green
skinned apple cultivars (e.g., ‘Granny Smith’) [64,65].
Figure 1. Schematic showing the classification of phytochemicals present in apple.
The most well-studied group of apple phytochemicals for their health benefits are
phenolic compounds [
54
]. Studies show that apples are an important source of phenolic
compounds in our diet contributing to 22% of phenolic intake [
55
,
56
]. Most of the phenolic
compounds in the fruit are usually present in the conjugated form such as glycosides or
esterified carboxylic acids. However, compared to other fruit, apples contain more of the
readily bioavailable free forms of phenolic compounds [
57
–
59
]. For instance, the ‘Red
Delicious’ apple had the highest level of free forms of phenolic compounds compared to
pear, plum, kiwifruit, and peach [60].
Phenolic compounds in apple can be sub-divided into two main groups (Table 1,
Figure 1) known as flavonoids and phenolic acids. Flavonoids can be further divided
into four structural subclasses including anthocyanidins, flavonols, dihydrochalcones, and
flavan-3-ols (flavanols) which can exist in the monomeric and oligomeric form [
49
,
61
]
(Table 1).
Phenolic acids include chlorogenic acid, hydroxycinnamic acid, and hydroxyben-
zoic acid [
49
,
61
]. In general, chlorogenic acid and monomeric and polymeric flavanols are
the major phenolic compounds, whereas anthocyanins and dihydrochalcones are minor
phenolic compounds of apples [
62
]. Moreover, anthocyanidins are responsible for the apple
redness [
63
,
64
]. Therefore, anthocyanidins are abundant in the apple cultivars with red
skin (e.g., ‘Red Delicious’) and are either present in low concentrations or absent in green
skinned apple cultivars (e.g., ‘Granny Smith’) [64,65].
There are differences in the distribution and type of phenolic compounds within
various parts of an apple such as peel, flesh, core, and seeds. The phenolic compounds
distribution and concentration in the peel and flesh of apples vary greatly due to genetic
diversity, maturity stage, growing conditions and geographical location, harvest, and
storage conditions [
59
,
66
–
70
]. However, studies have highlighted that there is a similar
phenolics distribution pattern for most apple cultivars (Figure 2).

Nutrients 2021,13, 4025 4 of 29
Table 1. Classification of apple phenolics.
Phenolics Group Phenolic Subgroup Phenolic Compounds
Flavonoids
Anthocyanidins
Cyanidin 3-O-arabinoside
Cyanidin 3-O-galactoside
Cyanidin 3-O-xyloside
Cyanidin 3-O-xylgalactoside
Flavonols
Quercetin
Quercetin 3-arabinopyranoside
Quercetin-3-arabinofuranoside
Quercetin 3-galactoside
Quercetin 3-glucoside
Quercetin 3-rhamnoside
Quercetin 3-rutinoside
Quercetin 3-xyloside
Dihydrochalcones
Phloretin
Phloretin-20-O-xyloglucoside
Phloridzin
3-hydroxyphloridzin
Flavan-3-ols
Monomeric
(+)-Catechin
(−)-Epicatechin
Oligomeric (Procyanidins)
Procyanidin B1
Procyanidin B2
Procyanidin B5
Procyanidin B7
Procyanidin C1
Phenolic acids
Chlorogenic acid
Hydroxy benzoic acid
Hydroxy cinnamic acid
In general, the apple peel contains about 2–4 times higher concentration of phenolic
compounds, and higher concentration of total procyanidins and total flavonoids, compared
to flesh [
71
]. Kalinowska et al. [
72
] demonstrated that apple peel from the ‘Gold Millennium’
apple contains five times the concentration of phenolic compounds compared to the
flesh [
68
]. Similarly, the peel of 15 different apple cultivars had greater concentration of all
phenolic compounds compared to the apple’s flesh [
73
]. In general, evidence from multiple
studies comparing various cultivars of apples has shown that apple peel contains all groups
of phenolic compounds and has greater concentration of procyanidins and total flavonoids
compared to the flesh [
59
,
74
–
76
]. However, there are some exceptions. Procyanidin B1
concentration in the flesh of ‘Gloster’, ‘Elstar’, and ‘Gala’ is higher compared to their
peel [
59
] and apple flesh of ‘Lodel’ is higher in phloridzin than its peel [
77
]. Quercetin
glycosides are usually found only in the peel [
73
]. On the other hand, chlorogenic acid can
be found in both the flesh and the peel of ‘Golden Delicious’, ‘Granny Smith’, and ‘Idared’
apples, but tends to be higher in the flesh [
59
,
69
]. These findings are in accordance with
the study from Kschnosek et al. [
73
], where the predominant group found in the flesh was
the phenolic acids (43%), while the flavonols, namely quercetin and its glycosides, were
enriched in the peel (72%) and not detected in the flesh. Taken together, these data suggest
that apple peel of most apple varieties contain more phenolic compounds than the flesh.

Nutrients 2021,13, 4025 5 of 29
Nutrients 2021, 13, x FOR PEER REVIEW 5 of 28
Figure 2. Phenolics distribution pattern in the peel and flesh of an average apple based on the data
from Lata, Trampczynska, and Paczesna [71], Tsao et al. [78], Lata [79], and McGhie et al. [62].
It is important to consider that apple peel contributes only up to 10% of the weight
of the whole fruit; therefore, the intake of some phenolic compounds from the peel after
consumption of a whole apple might not be as significant as the intake from the flesh.
Only a few studies have reported on the phenolic compounds content relative to the
weight of the peel compared to the whole apple [62,71]. McGhie et al. [80] demonstrated
that peel of ‘Braeburn’, ‘Royal Gala’, and ‘Red Delicious’ contributed 55%, 50%, and 52%,
respectively, of the apple’s total phenolic compounds. Similarly, apple peel of ‘Granny
Smith’, ‘Idared’, ‘Red Rome’, ‘Jonmac’, ‘Gloster’, and ‘Starking Delicious’ contributed 50%
or more to the apple’s total phenolic compounds content. In contrast, the peel of ‘Pilot’,
‘McIntosh’, and ‘Prima’ contributed less to the total phenolic compounds of the whole
apple [71]. Data from New Zealand heritage apple cultivar ‘Monty’s Surprise’ and the
commercial varieties ‘Braeburn’ and ‘Red Delicious’ (Table 2) showed that the contribu-
tion of total phenolics was lower from the peel compared to the flesh. However, anthocy-
anidins were only present in the peel and flavonols were only found in small quantities
in the flesh. Taken together, a combination of unpublished data from New Zealand (Table
2) and other published studies suggests that for most apple varieties the peel is a signifi-
cant source of phenolic compounds. Therefore, discarding the peel during production of
some traditional apple products, such as apple sauce [81], may decrease the health poten-
tial of the apples.
The health benefits of an apple’s bioactive compounds depend on their absorption,
metabolism, and distribution within the human body [82]. The bioavailability of phenolic
compounds (the fraction of the bioactive that has been absorbed and is available for bio-
logical activity) is affected by pH, enzymatic activity, their chemical structure, solubility,
free and bound form, and synergistic effects with the food matrix (see Section 5.2) [83–85].
Despite absorption of phenolic compounds beginning in the small intestine [85], most
of the compounds are released in and absorbed from the large intestine with aid from the
gut microbiota [84,86,87]. The gut microbiota is capable of transforming complex phenolic
compounds into metabolites that are more easily absorbed [88]. It was demonstrated that
once absorbed, phenolic compounds can be detected in human plasma and urine after
consumption of apple [89], apple juice [90], and apple cider [91]. Bioavailability of the
main apple phytochemicals is described in Section 5.2.
While apple is a rich source of nutrients and phytochemicals, there is evidence to
suggest that the apple food matrix (non-nutrient component) plays an important role in
the absorption and bioavailability of apple phytochemicals. Aprikain et al. [87] demon-
strated that the ingestion of phenolics-rich apple extract and apple fiber (pectin) together
Figure 2.
Phenolics distribution pattern in the peel and flesh of an average apple based on the data
from Lata, Trampczynska, and Paczesna [71], Tsao et al. [78], Lata [79], and McGhie et al. [62].
It is important to consider that apple peel contributes only up to 10% of the weight
of the whole fruit; therefore, the intake of some phenolic compounds from the peel after
consumption of a whole apple might not be as significant as the intake from the flesh. Only
a few studies have reported on the phenolic compounds content relative to the weight of
the peel compared to the whole apple [
62
,
71
]. McGhie et al. [
80
] demonstrated that peel of
‘Braeburn’, ‘Royal Gala’, and ‘Red Delicious’ contributed 55%, 50%, and 52%, respectively,
of the apple’s total phenolic compounds. Similarly, apple peel of ‘Granny Smith’, ‘Idared’,
‘Red Rome’, ‘Jonmac’, ‘Gloster’, and ‘Starking Delicious’ contributed 50% or more to the
apple’s total phenolic compounds content. In contrast, the peel of ‘Pilot’, ‘McIntosh’, and
‘Prima’ contributed less to the total phenolic compounds of the whole apple [
71
]. Data
from New Zealand heritage apple cultivar ‘Monty’s Surprise’ and the commercial varieties
‘Braeburn’ and ‘Red Delicious’ (Table 2) showed that the contribution of total phenolics was
lower from the peel compared to the flesh. However, anthocyanidins were only present in
the peel and flavonols were only found in small quantities in the flesh. Taken together, a
combination of unpublished data from New Zealand (Table 2) and other published studies
suggests that for most apple varieties the peel is a significant source of phenolic compounds.
Therefore, discarding the peel during production of some traditional apple products, such
as apple sauce [81], may decrease the health potential of the apples.
Table 2.
Estimated apple peel contribution to the total phenolics content in whole apple. Phenolic compounds were
measured using liquid chromatography-mass spectrometry (LC-MS, Dionex Ultimate RS3000 UHPL and a Bruker micrOTOF-
QII) in 2019, plant and food research, for 3 apple varieties—Monty’s surprise, Braeburn, and Red Delicious. Each compound
concentration was quantified by comparison with an authentic standard where possible or as equivalents to standard
compounds. Each phenolic compound in the table is presented as a percentage of total concentration measured using
LC-MS. Percentage total phenolics (percentage values presented in bold) was calculated based on the average weight of
whole apple (180 g) where apple skin contributed 18 g.
Monomeric
Flavanols Procyanidins Flavonols Dihydrochalcones Chlorogenic
Acid Anthocyanins Total
Phenolics
Cultivar Skin
(%)
Flesh
(%)
Skin
(%)
Flesh
(%)
Skin
(%)
Flesh
(%)
Skin
(%)
Flesh
(%)
Skin
(%)
Flesh
(%)
Skin
(%)
Flesh
(%)
Skin
(%)
Flesh
(%)
Monty’ Surprise * 33 67 29 71 94 6 42 58 10 90 100 n.e. 37 63
Braeburn 19 81 21 79 99 1 8 92 1 99 100 n.e. 31 69
Red Delicious 37 63 36 64 94 6 40 60 2 98 100 n.e. 46 54
* Monty’s Surprise—New Zealand’s heritage apple variety. “n.e.”—not evaluated (Anthocyanins were not evaluated in the flesh as they are
not present.).

Nutrients 2021,13, 4025 6 of 29
The health benefits of an apple’s bioactive compounds depend on their absorption,
metabolism, and distribution within the human body [
82
]. The bioavailability of phenolic
compounds (the fraction of the bioactive that has been absorbed and is available for
biological activity) is affected by pH, enzymatic activity, their chemical structure, solubility,
free and bound form, and synergistic effects with the food matrix (see Section 5.2) [
83
–
85
].
Despite absorption of phenolic compounds beginning in the small intestine [
85
], most
of the compounds are released in and absorbed from the large intestine with aid from the
gut microbiota [
84
,
86
,
87
]. The gut microbiota is capable of transforming complex phenolic
compounds into metabolites that are more easily absorbed [88]. It was demonstrated that
once absorbed, phenolic compounds can be detected in human plasma and urine after
consumption of apple [
89
], apple juice [
90
], and apple cider [
91
]. Bioavailability of the main
apple phytochemicals is described in Section 5.2.
While apple is a rich source of nutrients and phytochemicals, there is evidence to
suggest that the apple food matrix (non-nutrient component) plays an important role in the
absorption and bioavailability of apple phytochemicals. Aprikain et al. [
87
] demonstrated
that the ingestion of phenolics-rich apple extract and apple fiber (pectin) together had
greater effect on gut microbiota metabolism in the large intestine and lipid metabolism
than ingestion of the phenolics-rich apple extract alone, suggesting a beneficial interaction
between fiber and phenolic compounds [
87
]. Recent studies have shown that a whole apple
has strong prebiotic effects [
92
,
93
] and that its fiber content promotes the bioaccessibility of
other beneficial phytochemicals [
94
,
95
]. Additionally, dietary fiber fermentation by the gut
microbiota releases short chain fatty acids that have been shown to modulate expression of
cell cycle-regulating proteins and induce apoptosis in colon cancer cells [
96
]. The majority
of dietary fiber originates in the plant cell wall and many phytochemicals are known to
bind plant cell wall components [
94
]. As such, processing of apples (including juicing and
cooking) will influence the plant cell wall integrity and fiber content of the fruit, which will
consequently change the phytochemical’s bioaccessibility, bioavailabilty, and interactions
with the gut microbiota. However, processing and ultra-processing techniques are diverse
and complex and their impact on health is outside the scope of this review. The influence
of the food matrix (mainly fiber and carbohydrates) on the main apple phytochemicals is
described in Section 5.2.
The studies reviewed in this section highlight that there are large variabilities in the
composition of phytochemicals in apples and that the phytochemical patterns and profiles
can vary in relation to cultivar and apple part. Therefore, the type and level of health
benefit will vary in relation to the phytochemical profile of the apple consumed. Ultimately,
the phytochemical compounds from apple will only achieve benefit once they become
bioavailable and reach the cells and tissue of interest.
5. Health Benefits of Apple Phytochemicals: Cancer
Current research attributes the health benefits of apples mainly to the phenolic com-
pounds which exhibit several biological functions beneficial for human health [
54
]. Apple
phenolic compounds are believed to lower incidence of chronic conditions such as cardio-
vascular disease, cancer, asthma and pulmonary disease, diabetes, and obesity [
49
,
97
–
103
].
Apple phytochemicals are suggested to have many chemo-preventive and chemo-
protective effects (Figure 3) against various types of cancer. These effects include regulation
of proliferation, cell cycle, apoptosis, reactive oxygen species (ROS), and anti-inflammatory
activities [
36
,
47
,
86
,
104
,
105
]. In this section, we discuss the health benefits of apple phyto-
chemicals in relation to cancer from epidemiological studies, their ability to alter ROS in
cancer cells, and impact on cancer biology from in vitro and in vivo studies.

Nutrients 2021,13, 4025 7 of 29
Nutrients 2021, 13, x FOR PEER REVIEW 7 of 28
Figure 3. Main mechanisms of action of apple phytochemicals on cancer cells.
5.1. Epidemiological Evidence of Apple Consumption and Cancer Incidence
Epidemiological studies have associated apple and pear consumption with lower in-
cidence of different cancers. Reports from the European Prospective Investigation into
Cancer and Nutrition (EPIC) cohort study demonstrated that consumption of apples and
pears is associated with lower lung [106] and bladder [107] cancer incidence. Consump-
tion of apples and pears was also associated with lower lung cancer incidence in the Amer-
ican Nurses’ Health Study [108]. Apple consumption in particular was associated with
lower lung cancer incidence in epidemiological studies from [109], Hawaii [110], and the
Zutphen elderly study (Netherlands) [111]. Furthermore, consumption of apples and
pears has been associated with lower breast cancer risk from a pooled analysis of two
large prospective studies (Nurses’ Health Study—NHS and NHSII) [112]. In one case-con-
trol trial from Italy, it was reported that consumption of more than three apples or pears
a day was inversely related to pancreatic cancer [113], which is an extra fruit portion above
the dietary recommendation by WHO. Both apples and pears are rich in polyphenols, are
popular fruit, and are widely available all year round in many countries. Therefore, it is
not surprising that apples and pears are identified together in many observational studies
that assess dietary habits.
Apple consumption specifically was associated with lower cancer incidence in sev-
eral observational studies. Apple consumption was associated with decreased breast can-
cer incidence in a fruit and vegetable study conducted on pooled cohorts [114] and a case-
control study from Mexico in pre-menopausal women [115]. Similarly, consumption of
apples was associated with reduced incidence of colorectal [116], oral cavity and pharynx
[47,117], esophagus [47], larynx [47], ovary [47], renal [118,119], and prostate [47,120] can-
cers. One case-control study looking at fruit and vegetable consumption in pre-menopau-
sal women in Shanghai showed an inverse association with fruit intake and breast cancer
[121]. While the study found the strongest association was with citrus fruit, consumption
of 57 g/day of apple or more was also reported to reduce incidence of breast cancer in the
study [121]. In a meta-analysis of 20 case-control studies and 21 cohort studies, it was
shown that apple consumption was associated with a reduced risk of lung, colorectal, oral
cavity, and breast cancers [122].
Findings from the epidemiological studies reported in this review suggest that the
consumption of apples reduce cancer risk. However, the cohort size and composition as
well as the intervention vary between the different studies. Additionally, other dietary
and lifestyle factors could influence cancer outcome in these cohort and observational
studies. Further studies are needed to specifically clarify the effect of apple consumption
on the incidence of cancer. In addition, most of these studies are observational and to date,
there are no clinical intervention trials reported demonstrating the link between apple
Figure 3. Main mechanisms of action of apple phytochemicals on cancer cells.
5.1. Epidemiological Evidence of Apple Consumption and Cancer Incidence
Epidemiological studies have associated apple and pear consumption with lower
incidence of different cancers. Reports from the European Prospective Investigation into
Cancer and Nutrition (EPIC) cohort study demonstrated that consumption of apples and
pears is associated with lower lung [
106
] and bladder [
107
] cancer incidence. Consumption
of apples and pears was also associated with lower lung cancer incidence in the American
Nurses’ Health Study [
108
]. Apple consumption in particular was associated with lower
lung cancer incidence in epidemiological studies from [
109
], Hawaii [
110
], and the Zutphen
elderly study (Netherlands) [
111
]. Furthermore, consumption of apples and pears has been
associated with lower breast cancer risk from a pooled analysis of two large prospective
studies (Nurses’ Health Study—NHS and NHSII) [
112
]. In one case-control trial from
Italy, it was reported that consumption of more than three apples or pears a day was
inversely related to pancreatic cancer [
113
], which is an extra fruit portion above the dietary
recommendation by WHO. Both apples and pears are rich in polyphenols, are popular fruit,
and are widely available all year round in many countries. Therefore, it is not surprising
that apples and pears are identified together in many observational studies that assess
dietary habits.
Apple consumption specifically was associated with lower cancer incidence in several
observational studies. Apple consumption was associated with decreased breast cancer in-
cidence in a fruit and vegetable study conducted on pooled cohorts [
114
] and a case-control
study from Mexico in pre-menopausal women [
115
]. Similarly, consumption of apples
was associated with reduced incidence of colorectal [
116
], oral cavity and pharynx [
47
,
117
],
esophagus [
47
], larynx [
47
], ovary [
47
], renal [
118
,
119
], and prostate [
47
,
120
] cancers. One
case-control study looking at fruit and vegetable consumption in pre-menopausal women
in Shanghai showed an inverse association with fruit intake and breast cancer [
121
]. While
the study found the strongest association was with citrus fruit, consumption of 57 g/day
of apple or more was also reported to reduce incidence of breast cancer in the study [
121
].
In a meta-analysis of 20 case-control studies and 21 cohort studies, it was shown that apple
consumption was associated with a reduced risk of lung, colorectal, oral cavity, and breast
cancers [122].
Findings from the epidemiological studies reported in this review suggest that the
consumption of apples reduce cancer risk. However, the cohort size and composition as
well as the intervention vary between the different studies. Additionally, other dietary
and lifestyle factors could influence cancer outcome in these cohort and observational
studies. Further studies are needed to specifically clarify the effect of apple consumption
on the incidence of cancer. In addition, most of these studies are observational and to date,
there are no clinical intervention trials reported demonstrating the link between apple

Nutrients 2021,13, 4025 8 of 29
consumption and cancer incidence. Further research and clinical studies would help to
better understand and confirm the effect of apple phytochemicals on cancer in humans.
5.2. In Vitro and In Vivo Evidence of the Anticancer Properties of Apple Phytochemicals
Apple phytochemicals were reported to have significant effects on inhibiting mul-
tiple ‘hallmarks of cancer’ (detailed below) which are important in the progression of
cancer [123].
Phenolic compounds from different apple cultivars were positively associated with
the higher degree of inhibition of breast cancer cell proliferation [
124
–
126
] and induction
of cell cycle arrest [
125
,
127
]. Additionally, apple extracts inhibited growth of prostate [
127
]
and lung [
128
] cancer cells. Extracts of phenolics from apple pomace of different apple
cultivars were reported to inhibit proliferation of oral [
129
] and colon cancer cells [
58
]. In
addition to
in vitro
studies, apple polyphenol extracts also inhibited ex vivo proliferation
of a hepatoma cell line [130].
Multiple studies have demonstrated that apple phytochemicals can inhibit the ac-
tivity of p21, growth factors, pyruvate dehydrogenase kinases (PDKs), cyclin-dependent
kinases (CDKs), and extracellular protein kinases (ERKs) essential for cell cycle progres-
sion [
37
,
126
,
131
,
132
]. Furthermore, apple phytochemicals can also prevent cell cycle pro-
gression by activation of maspin, a tumor suppressor gene [
127
]. Reduced expression of the
key molecules essential for regulating cell cycle such as phosphorylated Rb, Cyclin D1, and
CDK4 by apple phytochemicals lead to cancer cells’ arrest [
125
,
127
]. Apple extracts were
reported to inhibit apoptosis in breast cancer cells [
124
,
128
]. Apple phenolic compounds
were shown to elevate the expression of pro-apoptotic genes such as p53 and Bax and re-
duction in the expression of anti-apoptotic genes such as p21 and Bcl-2 [
133
]. In addition to
inhibiting cell proliferation and promoting apoptosis, apple phytochemicals have also been
implicated in inhibiting angiogenesis by regulating VEGF [
123
] and inhibiting invasion
and metastasis [
58
,
130
] by regulating matrix metalloproteinases-2,-9 (MMP-2,-9), cadherins
and integrins [
123
], and regulating COX-2 a marker of inflammation [
123
]. Additionally,
the ability of apple phytochemicals to inhibit cell proliferation and in turn reduce incidence
of cancer was also observed in rats fed with one human apple equivalent. These rats had
reduced appearance of different precancerous markers (ACF, MDF, genes, and proteins
related to colorectal cancer progression) [
134
]. Similarly, the incidence of mammary tumors
in rats was reduced after two weeks of oral administration of 3.3, 10, and 20 g of apple
extract/kg of body weight, which correspond to the human consumption of one (200 g),
three, and six apples per day, respectively [135].
There is evidence that anticancer properties of apples are due to the synergistic
effects between apple phytochemicals and the food matrix [
136
–
139
]. Veeriah et al. [
136
]
demonstrated that colon cancer cells treated with an apple extract (extract from a mixture
of different apples) reduced cell proliferation to a greater extent compared to a synthetic
apple extract composed of eight apple phenolic compounds or individual apple phenolic
compounds. They further demonstrated that colon cancer cells treated with a synthetic
apple extract composed of eight apple phenolic compounds also reduced cell proliferation
to a greater extent compared to individual apple phenolic compounds. [
136
]. Results from
this study indicate the importance of the apple food matrix, which may contain other
bioactive compounds present in the apple extract but not in the synthetic mixture.
Taken together, evidence from
in vitro
, ex vivo, and
in vivo
studies suggest that apple
phytochemicals work synergistically to inhibit multiple ‘hallmarks of cancer’, which in turn
can influence cancer incidence and improve outcomes to chemotherapeutic treatments.
Oxidative stress can result in direct or indirect ROS-mediated damage of macro-
molecules such as DNA, proteins, and lipids, allowing cells to acquire multiple ‘hall-
marks of cancer’ and facilitating carcinogenesis [
55
,
140
,
141
]. Phenolic compounds such
as quercetin, epicatechin, procyanidin B2, phloretin, and chlorogenic acid were identified
as the biggest contributors to the apple’s antioxidant activity [
142
]. In one study, apples
showed the second highest antioxidant activity
in vitro
after cranberries among 11 common

Nutrients 2021,13, 4025 9 of 29
fruits tested [
57
]. Both apple peel and flesh extracts from dried and lyophilized apples of
four different cultivars reduced ROS in the lipopolysaccharide (LPS)-induced mouse brain
microglia cells (BV-2), with apple peel having a greater antioxidant effect [
143
]. While these
studies have indicated the antioxidant capacity of apples, it is important to note that the
methods used to measure antioxidant activity (such as total antioxidant capacity) are syn-
thetic assays and do not necessarily capture the complexity of a physiological system [
144
].
Nevertheless, it has been proposed that antioxidant activity of apple phytochemicals can in-
hibit or reduce cancer cell proliferation [
124
,
128
,
129
,
145
–
147
] and promote apoptosis [
148
]
of cancer cells based on in vitro studies (Table 3).
On the other hand, many bioactive compounds can work as prooxidants and under
certain conditions (high concentration, presence of metal ions, and low pH) can induce
ROS production and promote cell death [
149
–
151
]. In cancer therapy, prooxidants may
have a beneficial effect by working as cytotoxic agents for fast growing cells and inducing
cancer cell death [
152
–
154
]. Prooxidant activity of many phenolic compounds has been
associated with their ability to induce apoptosis and cell cycle arrest in different cancer
cells [
155
–
157
]. For example, Mendoza-Wilson et al. [
158
] demonstrated that phloridzin
exhibited prooxidant activity [
158
]. Catechin and epicatechin are well known antioxidants,
however, they can act also as prooxidants [
159
,
160
]. Epicatechin induced ROS production
in colon cancer cells led to activation of pro-apoptotic enzymes and therefore induced
apoptosis of these cells [159].
These examples suggest that some phytochemicals have a biphasic or hormetic re-
sponse depending on the dose administered [
161
]. Therefore, phytochemicals such as the
ones present in apple can be used to produce an antioxidant effect for cancer prevention,
but also induce prooxidant effects with benefits in cancer prevention.
In the subsequent sections. the review will focus on the anticancer mechanisms of
the main apple phenolic compounds (quercetin, phloretin, chlorogenic acid, catechins,
epicatechins, and procyanidins) and triterpenoids. The data on
in vitro
activity of apple
phenolics with effective concentrations are summarized in Table 3.
5.2.1. Quercetin Anticancer Properties
Of all the apple phenolic compounds, quercetin glycosides are the most efficiently ab-
sorbed compounds from apples [
162
–
164
], mainly absorbed in the large intestine. Quercetin
in apples is present in glycoside forms, and interestingly, these are more readily absorbed
compared to quercetins from tea [
165
] but less readily absorbed compared to the quercetins
from onion [
166
]. Quercetin glycosides can be absorbed as intact molecules where the
sugar moiety helps to improve absorption through the gut lumen [
167
]. Furthermore,
the presence of carbohydrates and pectin in the apple food matrix significantly increases
quercetin absorption [
168
–
171
]. Quercetin has been detected in the plasma of humans
(Cmax 0.30
µ
M/92 ng/mL, Tmax 2.5 h) [
166
] and rats (Cmax 118
µ
M
±
08) [
172
] after
apple consumption. These studies suggest that quercetin is absorbed and present in the
plasma at a sufficient concentration to elicit the anticancer effects.
Recent
in vitro
and
in vivo
studies have reported that quercetin is one of the flavonoids
responsible for the apple’s anticancer properties [
173
,
174
]. Quercetin has been shown to
inhibit cell proliferation of breast [
175
–
178
], ovarian [
179
], lung [
180
,
181
], and liver [
180
]
cancer cells
in vitro
(Table 3). Additionally, studies have demonstrated quercetin’s ability
to induce apoptosis in multiple cancer cell lines ([
177
,
178
,
182
,
183
], Table 3) and
in vivo
using colon cancer cell line xenografts in mice [
182
]. The ability of quercetin to promote
apoptosis and cell cycle arrest is believed to be due to its regulation of p53, GADD45, and
AMPK [
182
,
184
]. Autophagy is another form of cell death in which damaged organelles
are degraded [
185
]. Interestingly, quercetin is also shown to induce autophagy in lung
cancer cells [
181
] and in breast cancer bearing mice by reducing the activity of AKT-mTOR
pathway [
186
]. Additionally, quercetin inhibited invasion and migration of breast [
186
]
and colorectal [
187
] cancer cells (Table 3). Quercetin was also shown to inhibit the ac-

Nutrients 2021,13, 4025 10 of 29
tivity of VEGFR2 and therefore inhibit angiogenesis in breast [
188
], prostate [
189
], and
retinoblastoma [190] cancer cells.
Based on the results from
in vitro
studies, quercetin has strong anticancer properties
in different cancer cells. However, the absorption and metabolism of quercetin glycosides
from whole foods such as apples are not well known. Therefore, to better understand the
anticancer effects of quercetin in humans, further studies are needed to identify factors that
influence quercetin mechanisms of action and bioavailability in vivo.
5.2.2. Phloretin and Phloridzin Anticancer Properties
Phloretin and its glucoside form (phloridzin) are other flavonoids found in apple.
Phloretin and phloridzin are metabolized into phloretin glucuronides and phloretin sulfate
glucuronides in the human intestine [
169
]. Phloridzin has been detected in the plasma
(Cmax 66.9.0
µ
M
±
19.4, Tmax 10 h) and urine of rats [
191
,
192
]. It has also been detected in
the plasma of humans (Cmax 73 nM
±
11, Tmax 0.6 h) [
193
]. Phloretin and its glycosides
has been detected in ileal fluid in humans after consumption of apple juice [
194
] and
cider [
193
], whereas phloridzin was not detected, suggesting that phloridzin is more
readily absorbed.
Based on the available evidence, it is unclear how the apple food matrix and com-
position of the gut microbiota would affect uptake and metabolism of phloretin, which
in turn may impact its anticancer properties against cancer cells. Despite limited infor-
mation on the bioavailability of phloretin, several lines of evidence support its anticancer
properties from
in vitro
and
in vivo
studies. Phloretin was shown to inhibit proliferation
of breast cancer [
195
] and colorectal [
196
] cancer cell lines via inhibition of glucose trans-
porter 2 (Glut-2)
in vitro
and
in vivo
[
197
]. Additionally, phloretin inhibited proliferation
by promoting cell cycle arrest [
198
,
199
], ROS production [
200
], apoptosis [
198
,
201
–
203
],
and by inhibition of autophagy via mTOR/ULK1 [
204
]. Phloretin also inhibited invasion
and migration [
197
,
200
,
205
,
206
]. Moreover, phloretin promoted an anti-inflammatory en-
vironment by inhibiting the expression of pro-inflammatory molecules PGE2, IL-8 and
advanced glycation end products (AGEs) receptor [
207
]. Finally, evidence from
in vivo
studies suggest that phloretin may enhance the effect of commercial chemotherapeutic
drugs such as Paclitaxel [208].
Details of these
in vitro
and
in vivo
studies are provided in Table 3. It is important
to note that most of the
in vitro
cancer studies use synthetic phloretin, thus, to maxi-
mize the anticancer benefits of phloretin, there is a need to further our understanding of
phloretin bioavailability.
5.2.3. Chlorogenic Acid Anticancer Properties
Chlorogenic acid is one of the phenolic acids abundant in apples and is reported to
have anticancer potential, details of which have been summarized in Table 3. Chlorogenic
acid is metabolized mainly in the large intestine by the gut microbiota from its aglycone
form to its microbial metabolites, some of which include caffeic acid, 3-phenylpropionic
acid, 3-phenylpropionic acid, hippuric acid, and quinic acid [209–212]. Interestingly, after
consumption of foods rich in chlorogenic acid, its microbial products have been detected
in the plasma of rats (Cmax 0.34
µ
M, Tmax 1 h) and human urine [
209
,
210
,
213
] but not its
aglycone forms [
209
,
210
]. Studies
in vitro
and
in vivo
have demonstrated that chlorogenic
can inhibit cell proliferation [
214
–
218
], promote cell cycle arrest [
214
,
218
,
219
] via affecting
miR-17 family [
214
], induce apoptosis [
26
,
218
] by binding to annexin and suppressing
the NF-
κ
B pathway [
220
,
221
], and inhibit invasion and metastasis via downregulation of
MMP-2 and MMP-9 [
216
]. Chlorogenic acid also inhibited growth of the liver [
216
] and
breast [220,221] cancer tumor in xenograft mice in vivo.
Chlorogenic acid possesses different anticancer properties
in vitro
. However, the lim-
iting factor for its anticancer properties in humans is its low bioavailability. The microbial
produced metabolites of the gut might be contributors to the chemo-preventive effects of
chlorogenic acid, however, further research in this area is needed.

Nutrients 2021,13, 4025 11 of 29
5.2.4. Catechins and Epicatechins Anticancer Properties
Catechins and epicatechins are monomeric flavanols that are unstable in the gastroin-
testinal tract and poorly absorbed [
222
], with only 1.6% of the ingested catechins/epicatechins
from tea, detected in human plasma, feces, and urine (plasma epicatechin Cmax 174 nM,
Tmax 7 h) [
223
]. Similar results were obtained in the plasma of rats where the oral bioavail-
ability of radioactively labeled catechin was about 3% and for radioactively labeled epicate-
chins was 4% of the orally administrated dose (catechins: Cmax 30.40
±
1.80 ng/mL, Tmax
1.25 h; epicatechins: Cmax 196.5
±
18.1 ng/mL, Tmax 1.1 h) [
224
,
225
]. Notwithstanding
the limitation with their bioavailability, catechins and epicatechins have been reported
to have a multitude of anticancer properties summarized in Table 3. Both catechins and
epicatechins
in vitro
and
in vivo
have inhibited cancer cell proliferation [
226
–
228
], induced
cell cycle arrest by upregulating the expression of p21 [
229
] and inhibition of CDC25A [
226
],
induced apoptosis [227,229–233], and reduced invasion and migration [233].
In several of these studies, the catechins and epicatechins used were derived from
sources other than apple. However, the impact of the apple matrix and the gut microbiome
on the bioavailability of catechins and epicatechins remains unknown. Thus, further studies
are required to investigate the bioavailability and anticancer properties of epicatechins and
catechin from apples.
5.2.5. Procyanidins Anticancer Properties
Procyanidins are another group of oligomeric flavanols, which are abundant in apples
and have many anticancer properties. Procyanidin dimers from grape seed extract and cocoa
were detected in human plasma (Cmax 16
±
5 nM, Tmax 0.5 h; Cmax
10.6 ±2.5 nM
, Tmax
2 h) [
234
,
235
] but not rat plasma [
236
]. Moreover, larger procyanidins were not absorbed
efficiently by intestinal epithelial cells and are metabolized to low weight phenolic acids by
the gut microbiota [
237
]. It was reported that compared to other apple phenolics, procyani-
dins have a greater effect on cancer cell proliferation and apoptosis
in vitro [238,239]
. Like
their monomeric counterparts (catechins and epicatechins), procyanidins have been shown
in vitro
and
in vivo
to inhibit proliferation
[238,240–242],
induce cell cycle arrest [
238
,
240
,
241
],
promote apoptosis
[238,239,243,244]
, induce ROS
[245,246]
, inhibit migration [
242
], and an-
giogenesis [
247
]. In addition, procyanidins isolated from apple also inhibited breast [
239
]
and liver [
242
] cancer tumor growth in xenograft mouse. Table 3provides details of the
in vitro studies.
The bioavailability of procyanidins varies and is dependent on their structure and the
composition of the gut microbiome, where the metabolites may elicit the anticancer effects.
Therefore, to further understand the anticancer properties of procyanidins, studies are
needed to investigate the anticancer properties of their metabolites and their bioavailability
in humans.
5.2.6. Triterpenoids Anticancer Properties
Triterpenoids are another group of bioactive compounds found predominantly in
apple peel. Triterpenoids are suggested to contribute to anticancer activity, details of
which are summarized in Table 3. Triterpenoids consist of oleanolic acid and its iso-
mer ursolic acid and betulinic acid. Triterpenoids are known to have low bioavailability
and are poorly absorbed in the intestine [
248
,
249
]. It has been shown that only 2.3%
of orally administered betulinic acid was detected in mouse plasma (Cmax 3.1
µ
g/mL,
Tmax
2 h
) [
250
], while only 0.7% of orally administered oleanolic acid was detected in
rat plasma samples (Cmax
74.0 ±57.2 ng/mL
, Tmax 25 mins) [
251
]. In contrast, oleano-
lic acid has been detected in human plasma four hours after raisin consumption (Cmax
24.4 ±14.4 ng/mL
, Tmax 4 h) [
252
]. Like other apple phytochemicals, triterpenoids were
shown to inhibit proliferation
[253–260]
, induce apoptosis [
80
,
253
–
255
,
257
–
259
,
261
–
267
],
alter ROS production [
262
,
268
,
269
], inhibit invasion and metastasis [
255
–
257
,
270
–
273
], and
angiogenesis [270].

Nutrients 2021,13, 4025 12 of 29
Current research on apple phytochemicals is focused more on the anticancer properties
of apple phenolic compounds with relatively few studies looking at apple triterpenoids.
Future research on other triterpenoids and their derivatives present in apples such as
pomaceic acid (which is unique to the apples) or pomolic, euscaphic, and maslinic acid is
necessary to better understand the anticancer properties specific to apples.
Table 3. Summary of mentioned in vitro studies with the effective concentration.
In Vitro Effect Expression Markers
Affected
Effective
Concentration Cell Line Ref.
QUERCETIN
Lung cancer
Anti-proliferative ↓PDK3 55.90 ±2.25 µM A549 [180]
Anti-proliferative,
pro-apoptotic, autophagy
inhibition
↑LC3-II, SIRT 1, AMPK,
beclin 1
↓p62
100 µM A549, H1299 [181]
Breast cancer
Anti-proliferative, cell
cycle arrest
↑cyclin B1 and CDK-1
↓p21 10 µMSK-BR3,
MDA-MB-453 [175]
Anti-proliferative,
pro-apoptotic
↑
miR-146a, bax, caspase-3
↓EGFR
80 µM/mL, 50
µM/mL
(respectively)
MCF-7,
MDA-MB-231 [177]
Anti-proliferative,
pro-apoptotic ↓survivin 40 mg/mL MCF-7 [178]
Pro-apoptotic, cell cycle
arrest ↓Foxo3a, p53, GADD45 20 µM MDA-MB-231 [182]
Metastasis and invasion
inhibition
↓MMP-2,9, VEGF, PKM2,
GLUT1, LDHA, Akt,
mTOR
30 µMMCF-7,
MDA-MB-231 [186]
Angiogenesis inhibition ↓VEGF, Pin1 30 µM MCF-7 [188]
Colorectal cancer
Metastasis and invasion
inhibition,
anti-inflammatory
↑E-cadherin
↓MMP-2,9, p65, TLR4,
TNF-α, COX-2, IL-6
5,10, 20 µM Caco-2 [187]
Liver cancer
Anti-proliferative ↓PDK3 49.10 ±1.45 µM HepG2 [180]
Ovarian cancer
Pro-apoptotic ↑phospho-eIF2α, p53
↓Rad51 25, 50, 75, 100 µMOV2008, A2780,
GM9607 [183]
Anti-proliferative,
pro-apoptotic, cell cycle
arrest
↓survivin 30 mg/ml SKOV-3 [179]
Prostate cancer
Anti-proliferative,
angiogenesis inhibition
↓
Akt, mTOR, VEGFR2, S6
kinase 10-40 mmol/L HUVECs [189]
Retinoblastoma
Angiogenesis inhibition ↓VEGFR 25, 50, 200 µM Y79 [190]

Nutrients 2021,13, 4025 13 of 29
Table 3. Cont.
In Vitro Effect Expression Markers
Affected
Effective
Concentration Cell Line Ref.
PHLORETIN AND PHLORIDZIN
Lung cancer
Anti-proliferative,
pro-apoptotic, invasion
and migration inhibition
↑caspase-3,-9
↓Bcl-2, MMP-2,-9 25, 50, 75 µg/mL A549, H838, H520,
Calu-1 [205]
Pro-apoptotic, cell cycle
arrest
↑Bax, caspase-3, -9
↓Bcl-2 50, 100, 200 µM A549 [199]
Breast cancer
Anti-proliferative, cell
cycle arrest ↓GLUT-2 25, 50, 100, 150 µM MDA-MB-231 [195]
Anti-proliferative,
autophagy inhibition ↓mTOR, ULK1, LC3B-II 100, 200 µMMDA-MB-231,
MCF7, ERα+[204]
Colorectal cancer
Anti-proliferative, cell
cycle arrest
↑E-cadherin, p53
↓GLUT-2 100, 200 µM Colo 205, HT-29 [196]
Pro-apoptotic
↑caspase-3,-7, -9, Bax,
cytochrome C
↓Bcl-2
100 µmol/L HT-29 [206]
Anti-inflammatory ↓PGE2, IL-8, AGEs 50 µM CCD-18Co [207]
Liver cancer
Pro-apoptotic, invasion
and migration inhibition ↓GLUT-2, Bcl-2, Akt 200 µM HepG2 [197]
Pro-apoptotic
↑SHP-1
↓p-Akt, pERK, mTOR,
VEGFR2, p-JNK
25, 50, 100 µM
SK-Hep1,
Hep3B2.1-7, Huh7,
PLC5, HepG2
[201]
Prostate cancer
Prooxidant,
anti-proliferative,
migration inhibition
↑ROS
↓β-catenin, TCF4, FoxA2,
c-Myc, CISD2
20, 50, 100 µM PC3, DU145 [200]
Gastric cancer
Anti-proliferative,
pro-apoptotic, cell cycle
arrest
↓p-JNK, p-38 4, 8, 16 µM AGS [198]
Esophageal cancer
Anti-proliferative,
pro-apoptotic
↑BAX, p53
↓Bcl-2
60, 70, 80, 90, 100
µg/mL EC-109 [203]
Brain cancer
Anti-proliferative,
pro-apoptotic, cell cycle
arrest
↑p27
↓CDK-2,-4,-6, cyclin-D,-E 100, 200, 300 µM U87, U251 [202]

Nutrients 2021,13, 4025 14 of 29
Table 3. Cont.
In Vitro Effect Expression Markers
Affected
Effective
Concentration Cell Line Ref.
CHLOROGENIC ACID
Lung cancer
Anti-proliferative, cell
cycle arrest
↑p21, p53, and KHSRP
↓c-Myc, miR-17 family 25, 50 µM H446 [214]
Anti-proliferative,
pro-apoptotic
↓
cIAP1, cIAP2, binding of
annexin A2 to p50 and
actin => ↓NF-κB
25, 50, 100, 200,
400, 800 µMA549 [220]
Anti-proliferative,
pro-apoptotic
↑
Bax, caspase-3, p38, JNK,
annexin V
↓Bcl-2, SOX2
30, 50 µM A549 [215]
Breast cancer
Anti-proliferative,
pro-apoptotic, migration
and invasion inhibition
↓annexin, NF-κB, p65 10,20 µMMDA-MB-231,
MDA-MB-453 [221]
Colorectal cancer
Anti-proliferative, cell
cycle arrest, prooxidant
↑ROS, p53
↓ERK
125, 250, 500, 1000
µmol/L HCT116, HT29 [217]
Cell cycle arrest,
pro-apoptotic ↑caspase-3 250, 500, 1000 µM Caco-2 [219]
Liver cancer
Anti-proliferative, cell
cycle arrest, invasion, and
metastasis inhibition
↓MMP-2,-9, ERK1/2 250, 500, 1000 µM HepG2 [216]
Anti-proliferative, cell
cycle arrest
↑p21, p53, and KHSRP
↓c-Myc, miR-17 family 25, 50 µM Huh7 [214]
Kidney cancer
Anti-proliferative,
pro-apoptotic
↑caspase, Bax
↓Bcl-2, PI3K, Akt, mTOR 40 µM A498 [26]
Osteosarcoma
Anti-proliferative,
pro-apoptotic, cell cycle
arrest
↑ERK1/2 200, 400 µM U2OS, Saos-2 [218]
CATECHIN AND EPICATECHIN
Breast cancer
Pro-apoptotic
↑ZIP9
↓cAMP
agonists to membrane
androgen receptors
200 nM MDA-MB-468 [230]
Pro-apoptotic agonists to membrane
androgen receptors 21.4 nM T47D [231]
Anti-proliferative,
pro-apoptotic, antioxidant
↑IRK
↓ROS 40, 100 µg/mL MCF-10A [227]
Pro-apoptotic, prooxidant ↑ROS, Bad, Bax
150, 200, 250, 300,
350, 400, 450, 500
µM
MDA-MB-231 [232]
Colorectal cancer
Pro-apoptotic, migration
and invasion reduction
↑E-cadherin
↓ERK1/2, c-Myc,
β-catenin
12.5, 20 µM HT-29 [233]
Liver cancer
Anti-proliferative, cell
cycle arrest
↑p21, waf1/cip1
↓CDC25A
50, 75, 100, 125, 150
µMHepG2, Huh7 [226]

Nutrients 2021,13, 4025 15 of 29
Table 3. Cont.
In Vitro Effect Expression Markers
Affected
Effective
Concentration Cell Line Ref.
Biliary tract cancer
Pro-apoptotic, cell cycle
arrest ↑caspase, p21, gene dr5 20, 50 µM
CCSW-1, BDC,
EGI-1, SkChA-1,
TFK-1, MzChA-1,
MzChA-2, GBC
[229]
Prostate cancer
Pro-apoptotic
↑ZIP9
↓cAMP
agonists to membrane
androgen receptors
200 nM PC-3 [230]
Pancreatic cancer
Anti-proliferative,
pro-apoptotic, cell cycle
arrest
↑Bax
↓Ras, NF-κB, p65, Bcl-2,
Pi3K, Akt
25, 50 µM E6E7-Kras-st [228]
PROCYANIDINS
Breast cancer
Pro-apoptotic ↑cytochrome-c,
caspase-3,-9 25 µg/m
B16, BALB-MC.E12
[239]
Pro-apoptotic, migration
and invasion reduction
↑maspin, E-cadherin,
BRCA1
↓
DNA methyltransferases
50, 100, 150, 200,
250 µMMDA-MB-231 [243]
Pro-apoptotic n/a 50 µM MCF-7 [244]
Pro-apoptotic, cell cycle
arrest
↑Bax, caspase-3,-9
↓Bcl-2 31.5, 36.6 mg/mL MDA-MB-231,
MCF-7 [274]
Colorectal cancer
Anti-proliferative,
pro-apoptotic, cell cycle
arrest
↑caspase-3, ERK1/2, JNK
↓PKC 45 µg/mL SW620 [238]
Anti-proliferative,
pro-apoptotic, cell cycle
arrest
↑MMP-2,-9, caspase-3,-9,
ERK 1/2, MEK, Akt, PI3K
↓EGFR
10–60 µMCaco-2, HT-29,
HCT-15, HCT-116 [240]
Pro-apoptotic, prooxidant
↑caspase-3,-8,-9, Bax,
ROS, cytochrome-c
↓Bcl-2
80 µg/mL SW480 and SW620 [246]
Anti-proliferative, cell
cycle arrest, pro-apoptotic
↑ERK1/2, MEK, PI3K,
Akt
↓EGFR
10, 20, 30 µM Caco-2 [241]
Pro-apoptotic ↑PKB, Akt, ERK1/2, p38 2.5–20 µM Caco-2 [275]
Pro-apoptotic
↑caspase-3,-9,
cytochrome-c
↓PI3K, Akt, bad
2.5–50 µM Caco-2 [276]
Liver cancer
Anti-proliferative,
migration inhibition ↓Kv10.1 10, 100, 1000 µM HepG2 [242]
Prostate cancer
Pro-apoptotic, prooxidant ↑ROS, ERK1/2, AMPKα
25, 50 µM (PCa
LNCaP); 50, 100,
200 µM (22Rv1)
PCa LNCaP, 22Rv1
[245]

Nutrients 2021,13, 4025 16 of 29
Table 3. Cont.
In Vitro Effect Expression Markers
Affected
Effective
Concentration Cell Line Ref.
TRITERPENOIDS
Breast cancer
Anti-proliferative n/a n/a MCF-7 [260]
Anti-proliferative,
pro-apoptotic
↑Bax, cytochrome-c, p53
↓Bcl-2
2.57, 5.45 µM
(respectively)
MDA-MB-231,
MCF-7 [254]
Anti-proliferative,
migration and invasion
inhibition
↑caspase-3
↓MMP-2,-9, TIMP-2 5, 10, 20 µMMCF-7, 4T1,
MDA-MB-231 [256]
Anti-proliferative,
pro-apoptotic, migration
and invasion inhibition
↓aerobic glycolysis,
c-Myc, lactate
dehydrogenase A
(LDH-A), p-PDK1,
Caveloin-1
48.55, 19.06 µM
(respectively)
MDA-MB-231,
MCF-7 [255]
Anti-proliferative,
pro-apoptotic, migration
and invasion inhibition
↑GRP78, PERK
↓aerobic glycolysis,
c-Myc, β-catenin
5-50 µMMDA-MB-231,
BT-549, HBL-100 [257]
Anti-proliferative,
pro-apoptotic, autophagy
inhibition,
anti-inflammatory
↓PI3K, Akt, NF-κB
232, 221, 240
µg/mL
(respectively)
T47D, MCF-7,
MDA-MB-231 [258]
Cell cycle arrest,
pro-apoptotic, autophagy
↑p53, p21, AMPK
↓ERK1/2, glycolysis,
PKM2, HK2
20 µM
MCF-7,
MDA-MB-231,
SK-BR-3
[80]
Lung cancer
Pro-apoptotic,
angiogenesis inhibition
↑Bax
↓VEGF 25, 50 µg/ml A549, H460 [270]
Colorectal cancer
Anti-proliferative n/a n/a Caco-2 [260]
Invasion and metastasis
inhibition ↓cadherins, integrins 10, 20, 40, 80 µM SW620 [272]
Liver cancer
Anti-proliferative,
prooxidant
↑ROS
↓PI3K, Akt1, mTOR 10, 30, 100 µM [268]
Anti-proliferative n/a n/a HepG2 [260]
Invasion and metastasis
inhibition ↓cadherins, integrins 10, 20, 40, 80 µM HepG2 [272]
Anti-proliferative,
pro-apoptotic
↑p53, caspase-3
↓Bcl-2, Mcl-a mRNA 10, 20, 30 µMHUH7,
PLC/PRF/5, L02 [265]
Pancreatic cancer
Cell cycle arrest,
pro-apoptotic, autophagy
induction
↑Bax, ATG5, LC3-II
↓Bcl-2, RAGE 25, 50, 75, 100 µM MIA Paca-2 [266]
Prostate cancer
Pro-apoptotic
↑cytochrome-c, PARP,
p21, p53
↓NF-κB, Bcl-2, p65
10, 25 µM LNCaP, DU145 [263]
Anti-proliferative,
pro-apoptotic
↑survivin
↓Bcl-2, Bcl-xl, survivin,
PI3K, Akt, mTOR
LNCaP, PC-3 [259]

Nutrients 2021,13, 4025 17 of 29
Table 3. Cont.
In Vitro Effect Expression Markers
Affected
Effective
Concentration Cell Line Ref.
Cervical cancer
Pro-apoptotic, cell cycle
arrest, prooxidant
↑
ROS, p21, Bad, caspase-9
↓PI3K, Akt 30 µmol/: HeLa [262]
Ovarian cancer
Anti-proliferative,
pro-apoptotic
↑Bax, caspase-3,-8,-9
↓Bcl-2 44.47 µM A2780 [264]
Gallbladder cancer
Anti-proliferative, cell
cycle arrest, pro-apoptotic
↑Bax, cytochrome-c,
caspase-3,-9
↓Bcl-2
50 µmol/L GBC-SD, NOZ [267]
Brain cancer
Pro-apoptotic, migration
and invasion reduction
↑JNK signaling pathway,
caspases
↓enzyme MGMT
20 µM U373MG [273]
Anti-proliferative,
pro-apoptotic ↓enzyme MGMT, STAT3 20, 30, 40, 50 µMLN229, LN18,
T98G [253]
Osteosarcoma
Anti-proliferative,
pro-apoptotic, antioxidant
↑caspase-3
↓Notch signaling
pathway, Bcl-2, ROS
50, 80 µM
(respectively) Saos-2, MG63 [269]
Melanoma
Invasion and metastasis
inhibition ↓cadherins, integrins 10, 20, 40, 80 µM B16-F10 [272]
↑: increased expression; ↓: decreased expression.
6. Conclusions
Cancer is a leading cause of death globally and represents one of the greatest health
challenges. Therefore, it is necessary to find effective prevention tools to lower incidence of
this chronic disease. Phytochemicals are secondary metabolites present in vegetables and
fruit that provide many health benefits such as chemo-preventive and chemo-protective
effects in different cancers. As highlighted in this review, apples are a promising fruit to
consider in dietary plans for cancer prevention as they are widely available and contains
various beneficial phytochemicals. There is evidence from epidemiological studies that
regular apple consumption decreases the incidence of different cancers. However, from
these observational studies, it is difficult to distinguish the effects of apple specifically
from other lifestyle factors that influence cancer risk. The anticancer effects of apples are
believed to be mainly due to their phenolic compounds such as phloretin, quercetin and
its glycosides, chlorogenic acid, catechin, and epicatechin. However, while most of the
research is focused on phenolics, there is evidence that triterpenoids, which are present
mainly in apple skin, have significant chemo-preventive and chemo-protective effects. A
limiting factor of the apple’s anticancer benefits is their low bioavailability
in vivo
and
in humans.
Apart from the
in vivo
and
in vitro
studies that overwhelmingly support the impact
of apples in cancer prevention and inhibition, clinical interventions are lacking. Therefore,
in this review article, we describe some of the considerations that need to be accounted for
when using apples in an interventional setting or dietary plans. The levels and profiles of
phytochemicals in apple depends on many factors such as cultivar and maturity stage, but
also vary greatly within the apple parts (peel, flesh). Apple’s skin is known to be a rich
source of phenolics and significantly contributes to the health benefits of apples, therefore,

Nutrients 2021,13, 4025 18 of 29
consumption of whole apple with skin and consumption of different apple cultivars might
help to obtain greater anticancer effects. Furthermore, the food matrix components such
as fiber have an important role to play in the health benefits of apples and influence the
bioavailability of the apple phytochemicals.
Apple phytochemicals provide many beneficial health effects and could work as a
preventive tool in cancer. However, more research (especially
in vivo
and clinical studies)
is needed to confirm apple’s anticancer effects and bioavailability in humans.
Author Contributions:
Conceptualization, L.N., N.A.N., S.M. and J.H.; writing—original draft
preparation, L.N.; writing—review and editing, T.M., M.C., L.N., N.A.N., S.M. and J.H. All authors
have read and agreed to the published version of the manuscript.
Funding:
This research was funded by Heritage Food Crops Research Trust. S.M. was supported by
Maurice Wilkins Centre for Biodiscovery and HRC: Sir Charles Hercus Fellowship (21-030). L.N. is
supported by a Massey University Doctoral Scholarship.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Acknowledgments:
Massey University Doctoral Scholarship support for L.N., Heritage Food Crops
Research Trust.
Conflicts of Interest:
The authors declare no conflict of interest. Funding by Heritage Food Crops
Research Trust.
Abbreviations
AGEs Advanced glycation end products
Akt Protein kinase B
AMPK Activated protein kinase
ATG5 Autophagy protein 5
Bad Bcl2 Associated Agonist Of Cell Death protein
Bax Bcl2 Associated X protein
Bcl-2 B-cell lymphoma 2
BRCA1 Breast cancer 1 gene
cAMP Cyclic adenosine monophosphate
CDC25A Cell division cycle 25 A gene
CDK-1,-2,-4,-6 Cyclin dependent kinase
cIAP1,2 Cellular Inhibitor of Apoptosis Protein 1
cip1 CDK- interacting protein
CISD2 CISD2 gene
c-Myc Cellular myelocytomatosis oncogene
COX-2 Cyclooxygenase-2
EGFR Epidermal growth factor receptor
ERK, ERK1/2 Extracellular regulated kinase
FoxA2 Forkhead box protein A2
FoxO3a Forkhead box protein o3a
GADD45 Growth arrest and DNA damage-inducible protein
Glut1 Glucose transporter 1
GRP78 (BiP) Binding immunoglobulin protein
HK2 Hexokinase-2
IL-6,-8 Interleukin-6,-8
IRK The arabidopsis receptor kinase
JNK C-Jun N-terminal Kinase
KHSRP Kh-type splicing regulatory protein
Kv10.1 Kv10.1 potassium channel
LC3-II Light chain membrane protein
LDHA Lactate dehydrogenase A
LDH-A Lactate dehydrogenase A

Nutrients 2021,13, 4025 19 of 29
Mcl-1 Induced myeloid leukemia cell differentiation protein
MEK Mitogen-activated protein kinase kinase
MGMT Methylated-DNA—protein-cysteine methyltransferase
miR-146a Micro Ribonucleic Acid 146a
MMP-2,-9 Matrix metalloproteinase-2,-9
mTOR Mammalian target of rapamycin protein
NF-κB Nuclear Factor kappa B
p21, p65, p62, Protein 21,65,62,53,38,27
p53, p38, p27
PARP Poly [ADP-ribose] polymerase 1
PDK3,1 Pyruvate dehydrogenase
pERK R-like endoplasmic reticulum kinase
PGE2 Prostaglandin E2
Phosphor-eIF2αPhosphorylation of eukaryotic initiation factor-2 alpha
PI3K Phosphoinositide 3-kinase
Pin1 Prolyl isomerase
p-JNK Phosphorylated c-Jun N-terminal Kinase (JNK)
PKB Protein kinase B
PKC Protein kinase C
PKM2 Pyruvate kinase m2
rad51 RAD51 Recombinase (gene)
RAGE Advanced glycosylation end product-specific receptor
Ras Ras protein
ROS Reactive oxygen species
SHP-1 Protein tyrosine phosphatase shp 1
SIRT-1 Sirtiuin 1
SOX2 Sry-box transcription factor 2
STAT3 Signal transducer and activator of transcription 3
TCF4 Transcription factor 4 (gene)
TIMP-2 Tissue Inhibitor of Metalloproteinase 2
TLR4 Toll-like receptor 4
TNF- αTumor necrosis factor alpha
ULK-1 Unc-51 like autophagy activating kinase 1
VEGF Vascular endothelial growth factor
VEGFR Vascular endothelial growth factor receptor
Waf1 Wild type p53 activated protein-1
ZIP9 Zinc transporter 9
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