Volume 13 Number 2 February 2020 pp.

146–156 146
www.transonc.com

Whole Fruit Phytochemicals Charlotte A. Mintie *, Chandra K. Singh * and Nihal

Ahmad *, †
Combating Skin Damage and
*
Carcinogenesis Department of Dermatology, University of Wisconsin,
Madison, WI, USA; † William S. Middleton VA Medical
Center, Madison, WI, USA

Abstract
Skin is arguably the largest organ of the body and is continuously subjected to intrinsic, extrinsic, and
environmental stresses. Therefore, skin developed elaborate mechanisms to maintain homeostasis, including
antioxidant, antiinflammatory, and DNA damage repair capabilities. However, repeated and excessive stresses
can overwhelm these systems, causing serious cutaneous damages, including skin carcinogenesis.
Phytonutrients present in the diet possess a myriad of health-promoting effects by protecting skin from
damaging free radicals as well as by other mechanisms. Although many chemoprotective phytonutrients have
been shown to be efficacious individually, a combination of multiple agents could have synergistic response in
curtailing or preventing cutaneous damages. Here, we discuss the benefits of natural amalgamation of
phytonutrients in select fruits against skin damage including carcinogenesis. However, a majority of these studies
have been done in preclinical models. Therefore, clinical studies are needed to determine the human relevance of
the available preclinical data, especially in the human population who are at higher risk for skin cancers (e.g.,
organ transplant patients). In addition, detailed well-structured preclinical animal studies in the models of high-
risk skin carcinogenesis could also be useful toward informing the design for human trials.

Translational Oncology (2020) 13, 146–156

Introduction nonmelanoma skin cancer (NMSC), and cutaneous lymphomas [1].

Skin is the body's first line of defense from a variety of external Conveniently, there is potential to impact the health of the skin
stresses, such as environmental stresses, genetic alterations, and through positive lifestyle enhancement including protection from the
infections, which can impact the integrity of the skin. Therefore, skin sun, not smoking or consuming alcohol, managing stress, and
has evolved mechanisms ensuring adequate repair and replenishment improving dietary habits. In the United States, the USDA dietary
to counteract these damages. However, cumulative stresses can impair guidelines provide key recommendations for a healthy eating pattern
skin's defense systems to result in a variety of cutaneous disorders and in a 2000-calorie-per-day diet by consuming a variety of vegetables,
diseases. In 2013, over 27% of the population in the United States fruits, grains, dairy, proteins, and oils [2]. In this review, we provide
(nearly 85 million individuals) were seen by a physician for skin insight into the health benefits imparted by whole fruits or extracts of
diseases [1]. Unfortunately, thousands of deaths were linked to these critical components (i.e., stems and seeds) containing phytonutrients,
diagnoses with 60% being from skin cancers including melanoma, which promote skin health and the reduction of disease. We have also
discussed the mechanisms of the protective response of whole fruits
such as grapes, berries, pomegranate, apples, and tomatoes in
Address all correspondence to: Nihal Ahmad, PhD, Department of Dermatology, chemical-induced and ultraviolet (UV) radiationemediated cuta-
University of Wisconsin, Medical Sciences Center, 1300 University Avenue,
Madison, WI 53706, USA. E-mail: nahmad@wisc.edu
neous damage, including carcinogenesis. These phytonutrient-rich
Received 25 October 2019; Accepted 29 October 2019 foods afford protection by reducing DNA damage through enhancing
repair or acting as a sunscreen, reducing oxidative stress and
Published by Elsevier Inc. on behalf of Neoplasia Press, Inc. This is an open access article under inflammation, which play into each other to promote tumorigenesis
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1936-5233/19 [3,4], and enhancing skin barrier functions. The available data
https://doi.org/10.1016/j.tranon.2019.10.014 seem to support the concept that whole fruits can promote skin health
Translational Oncology Vol. 13, No. 2, 2020 Whole Fruit Phytochemicals Combating Skin Damage Mintie et al. 147

and impart protection against cutaneous damages, including cell types within the dermis and epidermis are responsible for a variety
carcinogenesis. of sophisticated cellular functions and complex crosstalk to maintain a
balanced state of homeostasis, thereby providing defense and
Skin Architecture corrective actions against endogenous and environmental stresses.
As the largest organ of the body, the skin itself is elaborately organized When cutaneous homeostasis is disrupted because of extensive
into three separate layers: hypodermis, dermis, and epidermis [5] damage, the deregulation of normal cellular processes can lead to skin
(Figure 1). These layers are responsible for protection, absorption, disorders including inflammatory diseases and neoplasms [1,8,9].
thermal, hormonal, and immune regulations; synthesis of biologically
relevant macromolecules; and aesthetics. The hypodermis is mainly Environmental Stresses Associated with
composed of adipocytes and connective tissue. The fibroblastic Cutaneous Damages
dermis contains hair follicles, glands, blood vessels, and nerve endings The environmental agents and factors that can damage skin
and is responsible for flexibility due to the presence of collagen-rich include radiations, heat and cold, chemical irritants including
connective tissue and is separated from the outermost epidermis layer pollutants in the air and water, household cleaners, car emissions,
by the basal lamina [5,6]. The epidermis is the mechanical, and other compounds. However, solar UV radiation is a major
water-proof boundary between the external environment and the environmental cutaneous offender and is shown to be a complete
milieu inte rieur [5]. Approximately 80% of the cells composing the carcinogen. As outlined in Figure 1, the UV rays that reach our skin is
epidermis are keratinocytes that continuously proliferate and UVA (90e99%), and a small portion is UVB (1e10%), whereas the
differentiate to renew the skin. These cells are organized into majority of UVC is absorbed by the stratospheric ozone, therefore not
functional layers characterized by shape, size, nucleation, keratin causing measurable skin damages. UVB that penetrates the epidermal
expression, and degree of differentiation [7]. The other portion of layer can be rapidly absorbed by cellular DNA leading to the creation
epidermal cells includes melanocytes responsible for pigment of mutagenic cyclobutane pyrimidine dimers (CPDs) and 6e4
production, sensory Merkel cells, and immune Langerhans cells. All photoproducts [10]. UVA reaches deep in the dermis where absorbed

Figure 1. Solar ultraviolet radiation and skin: Major wavelengths and their effects on the skin.
148 Whole Fruit Phytochemicals Combating Skin Damage Mintie et al. Translational Oncology Vol. 13, No. 2, 2020

photons promote oxidation reactions, generating reactive oxygen (BCL-2, survivin) and proliferation (cyclins, c-Myc) [22]. Increased
species (ROS) [11] and promoting the production of a key marker of inflammation and ROS can feed into each other to enhance
oxidative DNA damage, 8-oxo7,8-dihydroguanyl (8-oxodG), in downstream biochemical effects leading to accumulation of oxidative
guanine bases of DNA [12]. Many studies have linked these damage of proteins, carbohydrates, and lipids within the epidermis
detrimental UV-induced DNA damages to mutations in key and dermis after the skin's antioxidant response has been overpowered
regulatory oncogenes and tumor suppressors seen in skin cancers, [3,4].
such as p53 [13]. The solar UV radiations have many effects on the
physiology of the skin, potentially amounting to 10 4e10 5 lesions per
cell per day [14]. On injury, the upregulation of p53, also known as Skin Carcinogenesis
the “guardian of the genome” [15], causes keratinocytes to arrest the Skin carcinogenesis is a stepwise process with three distinct stages:
cell cycle and undergo damage response pathways, including initiation, promotion, and progression (Figure 2). Initiation can occur
nucleotide excision repair (NER), base excision repair (BER), through exogenous (chemical, UV radiation) or endogenous
double-strand break repair, and cross-link repair [16]. NER is (inflammation) factors when the cellular repair capacity is unable to
responsible for repairing lesions from exogenous sources, such as repair DNA damage, being irreversible [23]. CPDs are accountable
CPDs and 6e4 photoproducts, and BER removes endogenous for the majority of UVB-induced mutations, indicated by the
oxidative-induced base lesions, such as 8-oxodG [16]. However, presence of C to T or CC to TT transitions on regulatory genes, such
failure or lack of the early repair mechanisms can push the initiated as p53 [24]. UVA-induced mutations occur through AT to CG
keratinocytes to a hyperproliferative stage, ultimately leading to transversions caused by 8-oxodG [12,24]. Because of the mutation in
neoplastic transformation and cancer progression [17]. p53, continued exposure to UVB can lead to clonal expansion
Other environmental factors such as diesel fuel exhaust, chemicals, (promotion) of initiated mutated cells [25], which appear to have a
cigarette smoke, and ozone (O3) can also lead to oxidative stress by growth advantage over neighboring normal cells that will go through
the creation of ROS. The skin combats ROS by employing apoptosis [25e28]. In humans, primary precancerous skin lesions can
antioxidant enzymatic (glutathione peroxidase, superoxide dismutase, include actinic keratosis (AK), which harbors a high mutational load
catalase) and nonenzymatic (glutathione, a-tocopherol, vitamin E, when compared with normal skin [29].
vitamin C) molecules to maintain redox homeostasis [9]. However, The most common appearances of NMSC are basal cell carcinoma
when the accumulation of intrinsic and environmental factors (BCC) and squamous cell carcinoma (SCC), both of which arise from
overwhelm the skin's defenses, the detrimental effects of oxidative keratinocytes and are known as keratinocyte carcinomas, and are most
stress can lead to skin dysfunction. ROS include the superoxide anion prominent in Caucasians [8,12]. Unfortunately, there are no registries
(O2
), singlet oxygen ( 1O2), hydrogen peroxide, and the hydroxyl to track NMSC incidence; therefore, the available data on predicted
radical (OH ). The ROS can affect protein structure and function, incidence are based on epidemiological studies. Rogers et al. estimated
leading to changes in inflammation, cellular proliferation, and even 2,191,100 procedures in 1,336,800 individuals in 2012, but this has
cell death [9]. likely increased over the past years, as predicted by upward trends
of the preceding years [30]. Because NMSC development has a
long latency, many individuals do not develop lesions until later in life
Oxidative and Inflammatory Response o n
Cutaneous Injury (70e80 years) despite initiating UV signature mutations generally
When a cutaneous injury occurs, keratinocytes and fibroblasts secrete occurring in childhood [30]. NMSC also affects more men than
proinflammatory cytokines to recruit leukocytes to the site of injury, women [31] and is the fifth most costly malignancy to treat in the
causing inflammation. Inflammation is a self-limiting process; United States, totaling billions of dollars spent in treatment and care
however, deregulation leading to the persistence of cytokines and costs on an annual basis [32]. Although not as common, NMSCs can
chemokines results in chronic inflammation and/or immunosuppres- also occur at a younger age [33]. Interestingly, many deaths of
sion leading to various pathologies and has been suggested as a individuals diagnosed with NMSC are associated with the develop-
hallmark of cancer [3,18]. In addition, transient levels of ROS can ment of another cancer type, such as lung, prostate, breast, colon, and
activate signaling pathways leading to an inflammatory response, melanoma [34]. Therefore, it is critical to determine prevention early
which has been linked to the proinflammatory signal transduction on to protect all ages from disease development.
pathways, such as MAPK, PI3K/AKT, NF-kB, and AP-1 signaling The majority of skin cancer cases diagnosed are BCCs, affecting
(reviewed in Ref. [3]). more than 3 million individuals in the United States on an annual
The MAPK family includes ERK1/2, JNK1/2, and P38 kinases, basis [30]. Although not life threatening, BCCs are a slow-growing
which are downstream of RAS, activated in the presence of oxidative neoplasm that rarely metastasizes and have nearly 100% survival after
stress and also well documented for their role in cellular proliferation diagnosis [35], although, if left untreated, BCC can invade locally
and cancer [19]. MAPKs also activate many downstream targets [36]. SCC is the second most commonly diagnosed NMSC in the
including COX-2 and AP-1 [3,20]. AP-1 is a transcription factor United States with 200,000e400,000 new cases each year,
responsible for binding Jun and Fos dimers to control keratinocyte accompanied by 3000 disease-related deaths because of metastatic
proliferation, differentiation, and apoptosis, yet alteration in AP-1 disease [34,37]. Currently, the risk of SCC metastasis is reported at
response can lead to tumor development [21]. The increased 4% [38], yet this rate is 2e3 times higher in immunosuppressed
expression of the RAS protein also plays into PI3K activation and individuals, such as organ transplant recipients [39]. Many studies
further AKT modulation. NF-kB is responsible for the regulation of have sought to determine the shift from normal skin to AK, a
many genes involved in the initiation of inflammation, including precancerous lesion, to SCC. Although AK and SCC appear to have a
chemokines and cytokines (IL-1, IL-6, TNF), proinflammatory similar profile of dysregulated pathways, it is argued that AK could be
enzymes (COX-2, iNOS), and genes linked to cellular survival responsible for counteracting additional deleterious mutations
Translational Oncology Vol. 13, No. 2, 2020 Whole Fruit Phytochemicals Combating Skin Damage Mintie et al. 149

Figure 2. Ultraviolet radiation and skin cancer: Steps involved in skin carcinogenesis.

leading to SCC, therefore the latency of years before progression of possibility of added fats, sugars, and sodium. Whole fruits can be
the tumor [29]. fresh, canned, frozen, or dried [2]. According to the USDA, the most
Although the diagnosis of NMSC can indicate increased consumed fruits in America are apples, bananas, watermelon, grapes,
susceptibility to subsequent lesions, the goal of current treatments strawberries, oranges, peaches, cantaloupe, pears, blueberries, raisins,
is to completely eradicate the lesion while preserving the structure and and pineapple [2]. Fruits are packed with phytonutrients that have
function of skin, as well as aesthetics. Current treatments for NMSC antioxidant, antiinflammatory, antimutagenic, or anticarcinogenic
include surgical methods such as excision, Mohs micrographic effects. In the natural amalgamation within whole foods, phytonu-
surgery, curettage and electrodesiccation, laser ablation and cryosur- trients can synergistically provide health benefits, and many studies
gery, and nonsurgical radiation and photodynamic therapies. have already implicated beneficial effects in several chronic
Generally, surgical procedures are highly effective, with good pathological conditions, including cancers (reviewed in
cosmetic outcomes for treating low-risk lesions [40]; however, unlike Refs. [46e48]). Below, we discuss studies implicating the beneficial
excision and Mohs microsurgery, there is a higher risk of reoccurrence effects of whole fruits on skin diseases. Our discussion includes the
after other procedures due to the lack of histological evaluation available in vitro and in vivo data on the potential effects of whole fruit
validating complete tumor excision [41]. and fruit extracts, against skin diseases and disorders. Because of the
amount of available literature, we have limited our discussion on
Whole Foods in Chemoprevention grapes, black raspberries, blackberries, pomegranate, apples, and
Chemoprevention is defined as the use of natural or synthetic agents to tomatoes (Table 1).
prevent, suppress, or reduce the progression of cancer and can be
undertaken with single or multiple agents that interfere with Grape (Vitis vinifera)
numerous pathways in the carcinogenesis process [42]. Many Often characterized among one of the world's healthiest foods,
individual phytonutrients have demonstrated beneficial health effects. grapes have been cultivated for nearly 8000 years, and grape-derived
In our laboratory, previous studies have shown the protective effects wine has been deemed a highly valued commodity in many ancient
of the grape antioxidant, resveratrol, against UVB-mediated cultures [49]. Grapes have been extensively used in many cultures for
carcinogenesis [43e45]. However, as studies have continued to their medicinal value. The traditional Ayurvedic medicine, originat-
progress toward the utilization of natural products to benefit health, ing from the Indian subcontinent, utilized fermented grapes, for
the natural matrix of polyphenols and antioxidants in whole foods has example, in the form of “Drakshasava” tonic, against lethargy,
become more and more attractive. This is partially because of wider weakness, and cardiac disease [50]. Chromatographic evaluation of
human acceptance and because individuals can modify their dietary the Drakshasava indicated the presence of many polyphenols,
habits, rather than continuously ingesting supplements or using including resveratrol and pterostilbene [51]. Within the last century,
topical ointments/creams. the grape cure was propagated, with some criticism, by a South
Fruits and vegetables are well known for their high nutrient African dietician Johanna Brandt who promoted grapes as having
content. The prevailing dietary recommendation for fruits in the anticancer effects [52], and the “French paradox” gained popularity.
American 2000 total calorie diet is equivalent to two cups of fruits and This paradox describes the low heart disease rate of the French
vegetables [2]. Overall, it is suggested to ingest whole fruits or 100% population due to the consumption of wine, despite a high-fat diet
fruit juice, therefore preserving the nutrient-dense nature without the [53]. Since then, over 1600 compounds have been identified in
 150
Whole Fruit Phytochemicals Combating Skin Damage
Table 1. In Vitro and In Vivo Studies to Assess the Effects of Fruits in Skin and Skin Conditions.

Chemopreventive Constituents Experimental Model Dose of Chemopreventive Agents Dose of Carcinogen Reference

In Vitro Studies
Grape (Burgund Mare) seed extract HaCaT 10 or 20 mg/ml UVB (100 or 200 mJ/cm2) [59]
Black raspberry extract JB6 C1 41 with AP-1 luciferase reporter 50 mg/mL, 30 min prior UVB (2 kJ/m2) [67,68]
Black raspberry extract JB6 C1 41 with AP-1, or NF-kB, or p53 luciferase reporter 25 mg/mL, 30 min prior BPDE (2 mM) [68]
Black raspberry extract JB6 C1 41 with AP-1, or VEGF luciferase reporter, 25 mg/mL, 30 min prior BPDE (2 mM) [69]
or PI3K mutant
Blackberry (tropical highland) juice NHEK 1:300 or 1:500, 2 h prior, or immediately for 24 h UVB (25 mJ/cm2) [72]
Blackberry (tropical highland) juice Human reconstituted skin equivalent Topical (10 mL), 2 h prior, or immediately for 24 h UVB (25 mJ/cm2) [72]
Pomegranate fruit extract NHEK 10e40 mg/mL, 24 h prior UVB (40 mJ/cm2) [78]
Pomegranate extract (POMx) HaCaT 10e40 mg/mL, 24 h prior UVB (15 or 30 mJ/cm2) [79]
Pomegranate juice, oil, or extract EpidermTM FT-200 reconstituted human skin 1e2 mL, or 5e10 mg/0.1 ml/well, 1 h prior UVB (60 mJ/cm2) [80]
Apple peel extract JB6/AP/kB 1:10 to 1:640, 2 h prior TPA (20 nmol) or UVB (4 kJ/m2) [83]
In Vivo Studies
Grape (Muscat Bailey) stem extract BALB/c mice Topical (1 mg in 0.2 ml propylene glycol), daily UVB (120 mJ/cm2), 3 weekly for 1 month [58]
Grape (Campbell Early) stem extract C57BL Topical (50 mg/kg), daily, 1 week prior UVB (120 mJ/cm2), 3 weekly for 3 weeks [57]

Mintie et al.
Y-grape juice or ethyl acetate extract SENCAR Topical (10 or 20 mL) single dose TPA (1.7 nmol), single dose [60]
Y-grape juice or ethyl acetate extract SENCAR Topical (2 or 10), 2 weekly, 30 min prior, or oral, DMBA initiation (2.5 mg/animal) and TPA promotion [60]
ad libitum (2 or 10) (1.7 nmol) for 20 weeks
Grape seed proanthocyandins SKH-1 hairless mice Oral, ad libitum (0.2% or 0.5% in AIN-76A diet) UVB (180 mJ/cm2) 3 weekly for 24 weeks [63]
Grape (Burgund Mare) seed extract SKH-1 hairless mice Topical, (4 mg/cm2), 30 min prior, single dose UVB (240 mJ/cm2), single dose [55]
Grape (Burgund Mare) seed extract SKH-1 hairless mice Topical (2.5 or 4 mg/cm2), 30 min prior or post UVB, (240 mJ/cm2), daily for 10 days [56]
Grape (red, green, black) powder SKH-1 hairless mice Oral, ad libitum (3% or 5% in AIN-76A diet) UVB (180 mJ/cm2) 2 weekly for 28 weeks [64]
Grape (red, green, black) powder SENCAR Topical (1, 2, or 4 mg), 30 min post DMBA (100 nmol), 2/week (4 or 24 weeks) [61]
Powdered grape seed extract SENCAR Topical (1, 2, or 4 mg), 30 min post DMBA (100 nmol), 2/week for 4 weeks [61]
Grape (red, green, black) powder SENCAR Oral (1%, 2%, or 5% in AIN-93GA diet), 2 weeks prior DMBA (100 nmol), 2 weekly for 12 or 24 weeks [61]
Black raspberry extract SKH-1 hairless mice Topical (500 mg), immediately post UVB (2240 kJ/m2), 3 weekly for 25 weeks [70]

Translational Oncology Vol. 13, No. 2, 2020

Black raspberry extract SKH-1 hairless mice Topical (500 mg), immediately post UVB (2240 kJ/m2), single dose [70]
Blackberry extract SKH-1 hairless mice Topical (10% or 20%), one day prior UVB (100 mJ/cm2), 3 weekly for 10 weeks [71]
Pomegranate fruit extract CD-1 Topical (2 mg), 30 min prior TPA (3.2 nmol), single dose [73]
Pomegranate fruit extract CD-1 Topical (2 mg), prior to TPA DMBA (50 nmol), TPA (3.2 nmol) 2 weekly for 30 weeks [73,75]
Pomegranate seed oil CD-1 Topical (5%), 1 h prior DMBA (200 nmol), TPA (5 nmol) 2 weekly for 20 weeks [75]
Pomegranate fruit extract SKH-1 hairless mice Oral (0.2% in drinking water), 14 days prior UVB (180 mJ/cm2), single dose [76]
Pomegranate fruit extract SKH-1 hairless mice Oral (0.2% in water), 14 days prior up to termination UVB (180 mJ/cm2), 7 doses on alternating days [77]
Apple peel extract AP-1 luciferase reporter transgenic mice (C57BL/6  DBA2) Oral, ad libitum, in lieu of drinking water and topical, 6 daily TPA (5 mg) or UVB (10 kJ/m2), single dose on fourth day of APE [83]
Apple peel extract AP-1-luciferase reporter transgenic mice (C57BL/6  DBA2) Oral, ad libitum, in lieu of drinking water, 2 days prior DMBA (400 nmol), TPA (17 nmol) 14 days later, 2 [83]
weekly for 20 weeks
Tangerine tomato powder SKH-1 hairless mice Oral, (10% in AIN-93GA diet), 10 weeks prior UVB (2240 J/m2), single dose at week 10 [87]
Tangerine or red tomato powder SKH-1 hairless mice Oral, ad libitum (10% in AIN-93GA diet), through 35 weeks UVB (2240 J/m2), 3 weekly, weeks 11 through 20 [88]
Translational Oncology Vol. 13, No. 2, 2020 Whole Fruit Phytochemicals Combating Skin Damage Mintie et al. 151

grapes, including anthocyanins, catechins, resveratrol, lycopene, In one photocarcinogenesis study, female SKH-1 mice were subjected
quercetin, and melatonin, among others [48,54]. Many researchers to 180 mJ/cm 2 UVB three times weekly for 24 weeks while
have moved evaluating key features of the grape including the stem, consuming a diet enriched with grape seed proanthocyanidins. The
skin, and seed, while others have explored the benefits of the whole authors found that the proanthocyanidins inhibited UVB-induced
fruit. inflammatory mediators, including COX-2 and other cytokines in the
Filip et al. determined the protective effects of red grape seed in skin and tumor [63]. In a study from our laboratory, female SKH-1
UVB-induced damages using a prepared extract from the seed of V. mice were subjected to 180 mJ/cm 2 UVB twice weekly for 28 weeks
vinifera. The extract was assessed for polyphenolic content and while consuming diets enriched with freeze-dried GP at concentra-
topically applied at 4 mg/mouse/cm 2 30 min before a single dose of tions of 0, 3, or 5%. Dietary GP supplementation resulted in a delay
UVB (240 mJ/cm 2) on female SKH-1 hairless mouse skin. It was in the onset of tumors coupled with a marked reduction of tumor
found that the extract attenuated UVB-induced oxidative stress by multiplicity and volume. Further mechanistic evaluation of the
preventing damages by lipid peroxidation and nitric oxide, while tumors demonstrated that GP consumption led to enhanced
reducing caspase-3 activity [55]. They further evaluated the protective apoptosis and oxidative stress response while reducing proliferative
capacity of the topical grape seed extract by extending the study to 10 marker and lipid peroxidation [64]. In addition, GP treatment also
consecutive days of UVB exposure at 240 mJ/cm 2. The extract resulted in an enhanced NER repair capacity in the skin through the
effectively reduced CPDs, hyperplasia, cytokine release, and oxidative reduction of CPDs [64]. Collectively, grapes are one of the most
stress while increasing antioxidant response [56]. Utilizing a different promising whole fruits for health improvement. Currently, there are
portion of the grape, the Jang group has sought to evaluate the approximately 200 clinical trials within the United States that focus
efficacy of grape stem extracts in UVB (120 mJ/cm 2, thrice weekly for on grape products for health (Table 2).
three weeks)-induced cutaneous damages. Using the C57BL strain,
male mice were given the extract one week before dosing and Plants of the Genus Rubus
throughout the study. The treatment resulted in reduced lipid Fruits from plants of the genus Rubus, including black raspberry
peroxidation, neutrophil and mast cell infiltrations, and COX-2 (Rubus occidentalis) and blackberry (Rubus fruticosus), have been
expression while retaining the integrity of the skin [57]. In a associated with modulating many biological activities including
subsequent study, topical application of an extract from the Muscat antioxidant response and carcinogenesis [65]. The three main classes
Bailey A grape was tested for its potential effect against UVB (120 mJ/ of polyphenols in these fruits include anthocyanin, ellagitannins, and
cm 2, thrice weekly for one month)-mediated damages in male Balb/c phenolic monomers, inducing phenolic acids and flavonoids [66].
mice. It was found that the extract reduced oxidative stress through Huang et al. sought to explore the health-promoting effects of black
recovered glutathione peroxidase and superoxide dismutase levels raspberry, strawberry, and blueberry extracts on UV-irradiated mouse
while preserving the integrity of the skin and preventing DNA epidermal C1 41 cells. The methanol extract from black raspberries
damage. In addition, the extract reduced inflammatory response as (BRE) (R. occidentalis) appeared to be the most potent inhibitor of
indicated by reduced mast cell and neutrophil infiltration and UVB-induced NF-kB activation in the cells, as demonstrated by the
proinflammatory cytokines [58]. In an in vitro study, spontaneously suppression of IKK activation. The results from this study indicated
immortalized human keratinocyte HaCaT cells were irradiated with that MAPKs, and consequently AP-1 activation, were not affected;
UVB (25e300 mJ/cm 2). A protective effect was observed from therefore, the extract acted specifically on NF-kB [67]. A previous
Burgund Mare variety red grape extract at concentrations of 10 and study using a similar extract demonstrated a differential inhibition of
20 mg/mL, increasing viability of the cells while reducing lipid benzo[a]pyrene diol-epoxide (BPDE)einduced AP-1 and NF-kB in
peroxidation, apoptosis, and DNA photoproducts [59]. JB6 murine cells, suggesting an inhibition of carcinogen-caused
In an in vivo study, Kobayashi et al. sought to evaluate the tumor development [68]. A subsequent follow-up study suggested
protective effects of topical and dietary Y-grape juice and ethyl acetate that BRE reduced the expression of AP-1 and VEGF in BPDE--
extract from Vitis coignetiae Pulliat (Y-grape) on 12-O-tetradecanoyl- treated epidermal C1 41 cells through inhibition of PI3K/AKT
phorbol-13-acetate (TPA)-induced edema and 7, 12-dimethylben- pathway leading to anticarcinogenic effects of black raspberries [69].
zanthracene (DMBA)-TPA carcinogenesis. Six-week-old SENCAR Duncan and colleagues examined the in vivo effects of BRE on two
mice were given a single dose of TPA on the inner and outer surfaces SKH-1 hairless mouse models. The first acute damage study
of the ear. Both topical and oral treatments appeared to reduce edema subjected SKH-1 mice to one minimal erythemal dose of UVB
in a dose-dependent manner. In a subsequent experiment, mice were
subjected to DMBA-TPA carcinogenesis with topical Y-grape juice or
Table 2. Clinical Trials to Assess the Effects of Whole Fruit on Varying Diseases and Health.
oral extract supplementation. All grape treatments imparted
significant protection against tumorigenesis, as demonstrated by Clinical Trials
reduced tumor incidence, tumor number, and COX-2 activity [60].
Grape Pomegranate Apple Berry Tomato
Hanausek et al. performed a similar study utilizing the DMBA-T-
PAetreated SENCAR mice. Their experimental protocol involved Active, not recruiting 16 4 8 8 6
Completed 123 62 132 48 49
topical pretreatment with resveratrol, dietary freeze-dried grape Enrolling by invitation 1 1 3 0 0
powder (GP), or a continuous diet of GP in AIN-93G starting 2 Not yet recruiting 10 2 9 5 4
weeks before DMBA and continuing to 12 weeks. All treatments Recruiting 27 4 30 12 7
Unknown status 21 15 15 6 4
reduced tumor burden as well as COX-2 and DNA damage within Withdrawn 1 2 5 2 3
the skin [61]. Unfortunately, chemically induced skin carcinogenesis Terminated 1 0 4 0 1
is not very relevant to human situations, as the majority, ~90% of
Total 200 90 206 81 74
human NMSCs, are linked to UV radiation as a causative factor [62].
152 Whole Fruit Phytochemicals Combating Skin Damage Mintie et al. Translational Oncology Vol. 13, No. 2, 2020

(2240 J/m 2), followed by topical application of 500 mg of BRE, and hyperplasia, infiltration of leukocytes, and COX-2 expression. In
sacrificed 48 h later. BRE treatment was found to reduce neutrophil addition, apart from enhancing the repair of CPDs and 8-oxodG after
activation, edema, and oxidative DNA damage, suggesting the a single dose of UVB, PFE treatment increased p53 and p21
inhibition of many hallmarks of an acute inflammatory response that expression [76]. As a hallmark of skin carcinogenesis, hyperprolifera-
have been implied in skin cancer development [70]. In the second tion of epidermal cells was evaluated by proliferative markers PCNA
carcinogenesis model, SKH-1 mice were exposed to 2240 J/m 2 dose [76,77], and cyclin D1 [77], demonstrating a reduced proliferative
of UVB thrice weekly for 25 weeks. Each treatment was followed by index of PFE. Furthermore, PFE inhibited the UVB-mediated
the topical application of BRE. Here, the chemopreventive effects of activation of NF-kB as shown by increased accumulation of IkBa to
BRE were observed though reduced tumor counts, tumor volume, keep NF-kB/p65 tethered to the cytoplasm, and subsequent
and tumor-infiltrating CD4þ T cells [70]. Collectively, this indicates inhibition of NF-kB and IKKa activation [76,77]. The multiple
the antitumor properties of BRE are through alterations of an UVB dose study evaluated upstream regulators of NF-kB in the
inflammatory response. MAPK family. PFE treatment mediates the decrease in ERK1/2,
Comparatively, another study used blackberry extract (BBE) to JNK1/2, and p38 suggested that PFE may modulate the crosstalk of
evaluate the beneficial effect on SKH-1 hairless mouse skin [71]. multiple pathways that lead to increased cell survival, inflammation,
When topically applied the day before each UVB exposure (100 mJ/ proliferation, and apoptosis, therefore leading to the photoprotection
cm 2) alternating every other day for ten weeks, it was found that BBE of skin cells [77]. The beneficial effects of pomegranate were also
modulated the MAPK signaling pathway to protect against the investigated in vitro. Utilizing PFE and other pomegranate-derived
UVB-induced damages. The reduction of phosphorylated ERK1/2, products (juice and oil), multiple studies determined their effects
p38, and JNK1/2, was accompanied by inhibition of NF-kB nuclear against UVB-mediated damages to NHEK [78], immortalized
localization and subsequent inflammatory mediators COX-2, iNOS, HaCaT keratinocytes [79], and human reconstituted skin [80]. In
and prostaglandin E2 [71]. In addition, BBE suppressed CPD addition to the observed reduction of MAPK signaling, proliferation,
formation, as well as oxidative stress and subsequent 8-oxodG and DNA damage, PFE was shown to inhibit the phosphorylated
formation [71]. Calvo-Castro et al. utilized juice of the highland activation of c-Jun and c-Fos, and MMP proteins, which are linked to
blackberry (Rubus adenotrichos, BBJ), rich in ellagitannins, to the extracellular matrix and collagen breakdown [79,80]. Taken
determine protective effects against UVB-exposed human epidermal together, all of these studies demonstrate the protective capacity of the
keratinocytes and a human-reconstituted skin equivalent model. pomegranate fruit against skin damages, including skin cancer.
Although BBJ was unable to protect the cells against UVB-induced
loss of viability, protection against UVB-mediated baseline guanine Apple (Malus pumila)
oxidation and direct CPD damage was observed in both cell cultures The second-largest source of fruit phenolics in the United States is
and a 3D skin model, as well as an increase in PARP cleavage [72]. apples [81]. Apples have substantially more phenolic content in the
Overall, several studies demonstrated that raspberries and blackberries skin as compared with the remainder of the fruit. Unfortunately, in
possess potential against UV-mediated cutaneous damages, including the production of canned apples and applesauce, the peel is discarded
photocarcinogenesis via multiple mechanisms. [82]. The flesh contains catechins, procyanidins, and caffeic acid,
whereas the peel contains these all including quercetin glycosides
Pomegranate (Punica granatum) [82]. To determine the chemopreventive effects of fresh apples, Ding
Pomegranate is 80% juice and 20% seed, rich in anthocyanins and et al. determined the effects of apple peel extract (APE) against
hydrolyzable tannins [73,74]. Multiple studies have assessed the DMBA-TPA skin tumorigenesis in AP-1 luciferase reporter trans-
effects of pomegranate on cutaneous damages and skin carcinogen- genic mice (C57BL/6 crossed with DBA2). Mice were provided APE
esis. In one study, female CD-1 mice were given a topical application in the drinking water ad libitum two days before the initiating dose of
of 2 mg pomegranate fruit extract (PFE) in acetone, followed by TPA DMBA, then throughout the remainder of the study [83]. After 20
(3.2 nmol/mouse) application 30 min later, followed by sacrifice at weeks of biweekly TPA application, mice were euthanized. Although
specific time points [75]. Topical PFE inhibited the inflammatory the authors observed a similar percentage of mice developing tumors,
response to TPA as shown by the reductions of skin edema, those ingesting the APE had greater than 50% inhibition in the
hyperplasia, dermal neutrophils, and ornithine decarboxylase and number of papillomas present at the end of the study, accompanied
COX-2. Subsequently, a reduction in the activation of the MAPK by decreased tumor volume [83]. To determine if this reduction of
pathway was observed. The antitumor effects of PFE were observed tumorigenesis is relative to AP-1 activation, the authors performed a
against DMBA-initiated and TPA-promoted (2 weekly application) separate experiment utilizing the same transgenic mouse strain. In this
tumorigenesis in CD-1 mice. Not only had PFE extended tumor experiment, the mice were provided ad libitum access to APE in their
latency but also at the end of the study, 20% of PFE-mice remained water and were also given six topical applications of APE over six days.
tumor-free, and tumor counts were equivalent to a 64% inhibition Mice then received a single dose of TPA or UVB irradiation (10 kJ/
[73]. This study supported the chemoprotective effects of pome- m 2) on the fourth day, and skin biopsies were collected 24 or 72 h
granate against tumorigenesis as shown through a prior study, where later. By 72 h posttreatment, APE significantly inhibited the
CD-1 mice underwent the DMBA-TPA protocol and received topical activation of UVB- and TPA-induced AP-1 activation [83].
5% pomegranate seed oil [75]. Furthermore, in vitro validation in mouse epidermal JB6 cells treated
Furthermore, Gil and colleagues determined the protective effects with varying doses of APE and TPA (20 ng/mL) or UVB (4 kJ/
of PFE in SKH-1 hairless mice exposed to UVB. Two studies m 2) demonstrated the same trend of reduced AP-1 activation. The
provided PFE in the drinking water (0.2% wt/vol) for 14 days before observed effect on AP-1 in JB6 cells was accompanied by the
a single dose of UVB [76], or 7 alternate day doses of UVB (180 mJ/ reduction in ERK and JNK in the UVB-treated cells, and ERK in
cm 2 ) [77]. Oral feeding of PFE reduced cutaneous edema, TPA-treated cells. Moreover, APE also appeared to be a potent
Translational Oncology Vol. 13, No. 2, 2020 Whole Fruit Phytochemicals Combating Skin Damage Mintie et al. 153

Figure 3. Molecular mechanisms of whole fruit products involved in the prevention of carcinogenesis process related to skin
cancer. Arrows and red text indicate upregulation and/or activation, and lines with a blunt end and green text
indicate downregulation and/or inhibition.

scavenger for ROS and inhibited TPA-induced transformation of After 10 weeks of dietary tomato consumption and one UVB
cells. Therefore, this study demonstrated that apple peels could exposure (2240 J/m 2), female mice had higher levels of skin and
impart skin cancer chemopreventive effects through the reduction of blood carotenoids as compared with their male counterparts.
ROS and via modulating MAPK and AP-1 signaling [83]. Similarly, Furthermore, tomato-containing diet reduced CPDs and p53 positive
George and Rupasinghe investigated the efficacy of an apple flavonoid epidermal cells. However, the attenuation of UV-induced DNA
fraction, a flavonoid-rich ethanolic extract of the Northern Spy apple damage in males was associated with reduced inflammation and CPD
cultivar, against various carcinogen-induced toxicity in normal levels [87]. In a subsequent study by Cooperstone et al., a tomato diet
human bronchial epithelial cells. The study demonstrated that was given for a 35-week tumorigenesis study in mice. Mice received
apple flavonoids could reduce total ROS generation and protect UVB exposures (2240 J/m 2) three times weekly, which resulted in
against carcinogen-induced oxidative DNA damage and facilitate papillomas in male mice at 6e10 weeks and in females at 10e12
repair mechanisms [84]. However, only limited studies, mostly in weeks. Although there was no difference noted in the female cohort,
vitro, have been conducted in this area. Additional studies in multiple male mice of the tomato-based diets developed significantly fewer
in vivo models and human investigations are warranted. tumors than those on the control diet [88]. Although encouraging,
further detailed studies are needed to determine the potential
Tomato (Solanum lycopersicum) usefulness of whole tomatoes in additional models.
The beneficial health effects of tomatoes have been linked to the
presence of carotenoids, which are pigments giving the fruit its color. Conclusion
Lycopene, the primary carotenoid of tomatoes, has been shown to act Over the past decades, scientific evidence supporting healthy eating
as a scavenger of ROS [85]. Stahl et al. suggested that the lycopene in patterns being linked to reduced disease risk has grown monumen-
tomatoes, combined with other carotenoids and noncarotenoids, tally. In this review, we evaluated studies of multiple fruits and their
imparts a photoprotective effect against UV-dependent skin damage benefits to protect against cutaneous damages, including skin
[86]. A study by Kopec et al. utilized the SKH-1 hairless mouse carcinogenesis, suggestively because fruits are packed with phytonu-
model to comparatively analyze the difference among males and trients that possibly act synergistically to prevent oxidative and
females in photoprotection from UV when on a tomato diet [87]. inflammatory conditions, such as cancer and aging. Collectively, these
154 Whole Fruit Phytochemicals Combating Skin Damage Mintie et al. Translational Oncology Vol. 13, No. 2, 2020

studies have demonstrated the beneficial effects of utilizing whole [8] Apalla Z, Nashan D, Weller RB and Castellsague X (2017). Skin cancer:
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Disclosure Statement kinase signal transduction pathways activated by stress and inflammation.
The authors have no conflicts of interest to declare. Physiol Rev 81, 807e869.
[20] Kim AL, Labasi JM, Zhu Y, Tang X, McClure K, Gabel CA, Athar M and
Bickers DR (2005). Role of p38 MAPK in UVB-induced inflammatory
Acknowledgment responses in the skin of SKH-1 hairless mice. J Investig Dermatol 124,
This work was partially supported by funding from the California 1318e1325.
Table Grape Commission, as well as the National Institutes of [21] Eckert RL, Adhikary G, Young CA, Jans R, Crish JF, Xu W and Rorke EA
Health (grant numbers R01AR059130 and R01CA176748 to NA), (2013). AP1 transcription factors in epidermal differentiation and skin
cancer. J Skin Cancer 2013, 537028.
and the Department of Veterans Affairs (VA Merit Review Awards
[22] Bell S, Degitz K, Quirling M, Jilg N, Page S and Brand K (2003).
I01CX001441 and I01BX004221 and a Research Career Scientist Involvement of NF-kappaB signalling in skin physiology and disease. Cell
Award IK6BX003780 to NA). We also acknowledge the core Signal 15, 1e7.
facilities supported by the Skin Diseases Research Center (SDRC) [23] Pitot HC and Dragan YP (1991). Facts and theories concerning the
Core Grant P30AR066524 from NIH/NIAMS. mechanisms of carcinogenesis. FASEB J 5, 2280e2286.
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skin cancer. Toxicol Appl Pharmacol 224, 241e248.
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