Diet phytochemicals and cutaneous carcinoma chemoprevention: A review

Abstract

Cutaneous carcinoma, which has occupied a peculiar place among worldwide populations, is commonly responsible for the considerably increasing morbidity and mortality rates. Currently available medical procedures fail to completely avoid cutaneous carcinoma development or to prevent mortality. Cancer chemoprevention, as an alternative strategy, is being considered to reduce the incidence and burden of cancers through chemical agents. Derived from dietary foods, phytochemicals have become safe and reliable compounds for the chemoprevention of cutaneous carcinoma by relieving multiple pathological processes, including oxidative damage, epigenetic alteration, chronic inflammation, angiogenesis, etc. In this review, we presented comprehensive knowledges, main molecular mechanisms for the initiation and development of cutaneous carcinoma as well as effects of various diet phytochemicals on chemoprevention.

Graphical Abstract

1. Introduction

Till now, cutaneous carcinoma is the most common human malignancy (especially in the white population) due to steadily rising life expectancy, increasing urbanization and subsequent lifestyle changes, with millions of new cases detected worldwide each year [1-4]. Although the incidence rate for all cancer sites combined is decreasing, the cutaneous carcinoma incidence rate has continued to increase, which is a significant public health problem that exacts a substantial financial and social burden [5].

Cutaneous carcinoma is generally classified as malignant melanoma and non-melanocytic cutaneous carcinoma (NMSC). The latter includes squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) as the main subtypes that are named according to the originating cells and clinical behaviors [6]. NMSC are much more frequent than melanoma, but they have a better prognosis. Both, basal and squamous cell carcinomas, originate from epidermal keratinocytes and both appear mainly in cutaneous areas exposed to sunlight [7]. BCC accounts for the majority of NMSC cases (about 80%–85%) and has a low rate of metastasis to other organs, while 15%–20% of NMSC are SCC with a higher tendency to metastasize and higher mortality than BCC [8,9]. Melanoma, which is derived from epidermal melanocytes, represents only 4% of cutaneous carcinoma cases, yet accounts for 80% of all cutaneous carcinoma-related deaths [6]. Limited progress has been made in the treatment of cutaneous carcinoma over the past 4 decades, through the use of immunotherapy, chemotherapy, radiotherapy, targeted therapy and combinations, which have yielded reduced response rates and low median survival, associated with significant toxic profiles and treatment resistance. Thus, the burden of cutaneous carcinoma remains chronically high [10,11,262].

Development of cutaneous carcinoma is a multistep process that involves initiation, promotion and progression (Graphical abstract). Mutation and abnormalities of key cellular regulators (e.g. RAS, p53, EGFR and p16INK4A), as early events in tumorigenesis, are caused by various carcinogens (eg. UV) directly or through inducing epigenetic alterations and intracellular oxidative stress [12]. Due to subsequent failure of these genes, an accumulating cellular malignant phenotype may appear by activating transcriptional factors such as NF-κB, β-catenin, STAT3, HIF-1α and AP-1, as well as their downstream proteins. As a result, cutaneous carcinoma can be discerned owing to the inflammatory microenvironment together with uncontrollable cell growth and differentiation [13]. Besides, continuous inflammatory conditions and disturbed transcriptional factors activation may further lead to tumor-related angiogenesis and metastasis that are significant pathological indicators of lethal cutaneous carcinoma. Chemopreventive strategies have been reported to control such hyperactive signaling cascades and pathological alterations which may delay and reverse these multistep process of cutaneous carcinoma and lower the burden [14-16].

Over two-thirds of human cancers may be prevented by appropriately modifying the lifestyle, especially by changing the dietary habit [17]. Being responsible for color and other organoleptic properties, diet phytochemicals are chemical compounds naturally constituted in plant-based food [17-19]. Resveratrol, epigallocatechin gallate (EGCG) and curcumin have been reported to directly regulate a variety of molecular signal transduction pathways, which participate in cancer initiation, promotion or progression. Eventually, they can reduce the incidence and death rates of human neoplasms, such as cutaneous carcinoma [20-22].

In this review, we introduced the basic knowledge of cutaneous carcinoma, and highlighted the causative factors and their influences on the intracellular signaling cascades involved in cancer development. In addition, we shed light on some phytochemicals capable of targeting the signaling pathways which make them applicable to cutaneous carcinoma chemoprevention and control of its progression. On this basis, we also expounded the potential correlation between the these compounds and clinical outcome.

2. Risk factors for cutaneous carcinoma

High awareness of the risk factors for cutaneous carcinoma is crucial for prevention. Although why the incidence and death rates of cutaneous carcinoma have ascended so dramatically in recent years remains unclear, they may be attributed to multiple endogenous and exogenous factors. The most common risk factors are discussed as follows.

2.1. UVR

The vast majority of cutaneous carcinoma are caused by UV exposure from the sun and/or indoor tanning devices [23-26,264]. Reducing sun exposure by using sun-protective behaviors (ie, using sunscreen regularly; wearing protective clothing, wide-brimmed hats, and sunglasses; seeking shade; and limiting time outdoors during midday hours when UV radiation from the sun is most intense) can sharply reduce the lifetime risk of developing cutaneous carcinoma [27-29,264]. When UV is transmitted through the skin and absorbed by chromophores therein, a series of photochemical reactions are initiated, inducing direct photic damages to DNA, lipids and proteins. After being absorbed directly by cellular DNA, UV leads to DNA lesions primarily through cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4)-pyrimidone photoproducts, which are able to cause CC to TT or ‘UVR signature’ C to T mutations in multiple suppressor genes or oncogenes, such as p53, p16, Notch1, Nsd1 and mismatch-repair genes [30-33]. Additionally, UV also induces the production of reactive oxygen species (ROS) to cause indirect oxidative damage to DNA and proteins. Moreover, UV also can affect signaling pathways related to protein kinases (MAPKs and Akt), cell-cycle regulatory proteins, inflammatory enzymes and growth factors, which can thus tremendously affect the initiation and promotion of cutaneous carcinoma [34-38].

2.2. Immunosuppression environment

Immune system undergoes key events in detecting and clearing early aberrant cellular and molecular changes that may lower the risk of cutaneous carcinoma, so an opposite result occurs after the system is suppressed [39]. Medically induced immunosuppression, which is common among organ transplant recipients, is well-documented as a significant risk factor for cutaneous carcinoma [40]. Compared with the non-transplanted population, the risk of SCC rises 65- to 250-fold in transplant recipients, and that of BCC increases 10- to 16-fold [41,42]. PUVA light treatment and radiotherapy, which participates in many aspects of medical treatment, exerts suppressive effects on the cutaneous immune system by (1) impairing contact and delayed-type hypersensitivity reactions, (2) weakening antigen-presenting cell function, and (3) inducing the production of immunosuppressive substances such as interleukin (IL)-10, prostaglandins and ROS [43,44].

2.3. Inflammatory cutaneous condition

Inflammation of the skin increases the blood flow, which generates various growth factors and cytokines as well as results in inflammatory cell infiltration, thereby enhancing the growth of SCC and BCC [45]. The infiltrated inflammatory cells cause DNA damage by producing ROS, and the growth factors contribute to the uncontrollable proliferation of cells. Patients with inflammatory bowel disease (IBD) are also reported at increased risk from cutaneous carcinoma [46]. Both preclinical and clinical studies have estimated that anti-inflammatory drugs (e.g. aspirin) could influence on cutaneous carcinoma [47-49].

2.4. Chemical carcinogenic factor

Recently, the number of cutaneous carcinoma cases keeps rising annually owing to exposure of human bodies to chemical carcinogens. With city industrialization, arsenic has contaminated the drinking water for tens of millions of people around the world. In addition to affecting the whole body, chronic arsenic poisoning causes pigmentary changes of the skin, thus disrupting ATP production, hindering DNA repair that highly depends on energy and finally leading to cutaneous carcinoma [50,51].

2.5. Dermatologic diseases

Dysplastic nevus syndrome, which also known as the atypical mole syndrome, is often bound up with the melanoma. Dysplastic nevi raise the malignant melanoma risk 500-fold [52]. As a rare genetic condition affecting skin, endocrine, central nervous, and skeletal systems, basal cell nevus syndrome develops numerous BCCs in a single lifetime, usually beginning from puberty [53-55]. Xeroderma pigmentosum, as another inherited disease that affects the cutaneous ability to recover UVR damage, also elevates the risk of developing cutaneous carcinoma, at an earlier age in particular [56,57].

3. Preventable molecular pathways for cutaneous carcinoma and chemopreventive phytochemicals

Like many other cancer types, cutaneous carcinoma chemoprevention at the molecular level is typified by the disruption of, or at least the delay of, multiple processes and pathways among three carcinogenesis stages, i.e. initiation, promotion and progression [17,58]. According to this, potentially chemopreventive chemicals or biomolecules can be divided into blocking agents and suppressing agents [58].

3.1. Cutaneous carcinoma chemopreventive phytochemicals as blocking agents

By inhibiting the initiation stage, cancer chemopreventive molecules play an important role in the preservation of DNA in its native state. They can circumvent permanent, irreparable DNA damage that takes place during initiation by inactivating or metabolizing carcinogens [59]. Functioning as free-radical scavengers, they physiologically induce antioxidative system and trigger DNA repair [60]. Furthermore, blocking agents are also capable of modifying the epigenetic landscape [61].

3.1.1. Antioxidant activity

Many human epidemiological studies have demonstrated a highly close association between cutaneous carcinoma and chronically oxidative conditions, which caused by UV radiation, infection and chemical agents and can be detected commonly in earlier phase of cancer development [62]. Increased production of oxidative stress has been implicated in cancer development primarily through direct DNA mutation [63,64]. Additionally, this stress can affect protein conformations and functions together with transcription factor DNA binding by modifying the redox status of cells, thus altering gene expression [64,65]. In the meantime, the promotion of angiogenesis and metastasis as well as carcinogen metabolism can also be obviously affected [66]. Consequently, antioxidants can inhibit the onset of cutaneous carcinoma predominantly [64]. This kind of substances exert protective effects not only by directly scavenging ROS, but also by inducing de novo expressions of genes that encode defensive/detoxifying proteins, including phase II enzymes (e.g. γ-GCS, GPx, NQO, GST and HO-1) which is often diminished or become inadequate to alleviate cutaneous cellular canceration induced by radiation or some chemical carcinogens [67,68]. The 5′-flanking regions of these enzyme genes all contain a cis-element, also known as the antioxidant-responsive element (ARE) [69,70]. Many basic leucine zipper transcription factors, can bind ARE sequences and stimulate the expressions of the stress-response genes mentioned above. Notably, Nrf2 is the most important transcription factor that heterodimerizes and binds ARE sequence [71].

Nrf2-knockout mice, which showed greater sensitivity to carcinogenesis, failed to induce the expressions of many genes involved in carcinogen detoxification and protection against oxidative stress/cutaneous cellular vicious transformation [72-75]. Thus, chemopreventive phytochemicals which can eventually protect against cellular oxidative stress directly or activate Nrf2 signaling, could be employed as blocking agents for cutaneous carcinoma [76]. In the Nrf2 pathway, Kelch-like-ECH-associated protein 1 (Keap1), a cytoplasmic repressor of Nrf2, inhibits this transcription factor accumulates into the cell nucleus. Nrf2 is normally sequestered in the cytoplasm through a hydrophilic region in the NEH2 domain and the double glycine-rich domains of Keap1, which basically resembles the proteasome system for proteasome degradation and ubiquitination [77]. The cysteine residues of Keap1 can be oxidized or covalently modified (R) by antioxidant agents, so that Nrf2 is released from the Nrf2-Keap1 complex [78,79]. Sulforaphane, a well-studied isothiocyanate in broccoli, was found to protect cutaneous tissue from UVB-stimulated photodamage and prevent papilloma formation and JB6 P⁺ cell canceration only with Nrf2^wt presence induced by carcinogens through forming a covalent adduct with Keap1 protein at cysteine 151 and accelerating translocation of Nrf2 eventually [80-83]. Additionally, phosphorylation of Nrf2 in serine (S) and threonine (T) residues by upstream protein kinases (e.g. PKC, Akt, MAPKs and AMPK) can facilitate the dissociation of Nrf2 from Keap1 and translocation to the cell nucleus thereafter [84-86]. Lycopene, a carotenoid compound derived from tomato, was found a chemomodulatory efficacy on antioxidant enzymes (CAT, SOD, GR, GPx and HO-1) and DMBA/TPA-induced cutaneous carcinoma in our preliminary studies [87], and the mechanism was related to activate p38 MAPK and PKC (unpublished observation). In addition, direct binding partners other than Keap1 can bind with Nrf2 at the DLG and ETGE motifs to stabilize Nrf2 and thus conferprotection against oxidative stress, such as p21 and caveolin-1 [88]. In our group, one of my colleague has confirmed that DADS (diallyl disulfide), a major garlic derivative can inhibit TPA-induced tumor promotion by means of promoting Nrf2 nuclear localization in mouse skin, which seemed to be mediated through suppressing degradation of Nrf2 via upregulation of p21 protein level [89].

Till to date, numerous additional cutaneous carcinoma prevention studies have been done with a wide variety of anti-oxidant phytochemicals isolated from dietary plants, such as zerumbone from subtropical ginger, curcumin from turmeric, etc. Fig. 1 and Table 1 summarize representative cutaneous carcinoma chemopreventive dietary products capable of activating Nrf2 and inducing the expression of epidermal cytoprotective proteins.

Fig. 1.

Potential molecular targets of anti-oxidant diet phytochemicals for cutaneous carcinoma chemoprevention.

Table 1.

Cutaneum-specific induction of Nrf2 activation and/or its target protein expression/activity by some chemopreventive phytochemicals.

Phytochemicals	Origin	Cell or animal models	Effect	Mechanism
Sulforaphane	Broccoli; cabbage; cauliflower; kale	DMBA/TPA-induced cutaneous tumor in mice	Cutaneous papillomagenesis↓	Nrf2 signal pathway↑, HO-1 ↑ [81]
		UVB-induced cutaneous photodamage in mice HaCaT	Cutaneous inflammation↓ Cellular defense↑	Nrf2 signal pathway↑ [83]
Curcumin	Turmeric	Inorganic arsenite-stimulated HaCaT cell	Acute cytotoxicity↓	Nrf2 signal pathway↑, NQO1↑, HO-1↑, GCL↑, γ-GCS↑ and catalase↑ [82] Nrf2 signal pathway↑, NQO1↑, HO-1↑ and GCLM↑ [90]
Lycopene	Tomato	DMBA/TPA-induced cutaneous tumor in mice	Cutaneous papillomagenesis↓	Nrf2 signal pathway↑, GSH↑, ROS↓, MDA↓ and anti-oxidant enzymes↑ [87]
Resveratrol	Red grape	UVA radiation-induced HaCaT cell photodamage	Cell apoptosis↓	Nrf2 signal pathway↑, Keap-1↓ and anti-oxidant enzymes↑ [91]
Phenylethyl isothiocyanate (PEITC)	Crucifer	UV radiation-induced HaCaT cell photodamage	Cell apoptosis↓	Nrf2 signal pathway↑, NQO1↑, HO-1↑, GCL↑, γ-GCS↑ and catalase↑ [92]
Zerumbone	Tropical ginger	DMBA/TPA-induced cutaneous tumor in mice	Cutaneous papillomagenesis↓	Anti-oxidative and phase II metabolizing enzymes↑ [93]
		TPA-induced JB6P+ cell transformation	Grade malignancy↓	Nrf2 signal pathway↑ and HO-1↑ [94]
Ellagic acid	Blackberry, raspberry, strawberry	UVA radiation-induced HaCaT cell photodamage	Cell apoptosis↓	Nrf2 signal pathway↑, Keap-1↓ and anti-oxidant enzymes↑ [95]
Quercitrin	Oak bark	TPA and UVB-induced JB6P+ cell transformation	Grade malignancy↓	Nrf2 signal pathway↑ MAPKs↓ [96]
Quercetin	Onion, apple, red wine, tea	UVA radiation-induced HaCaT cell photodamage	Cell apoptosis↓	Nrf2 signal pathway↑ [97]
Thymoquinone	Black seed	TPA-induced cutaneous injury in mice	Cutaneous inflammation↓	Nrf2 signal pathway↑, HO-1↑, GST↑ and NQO1↑ [98]
Myricetin	Waxberry	UVB-induced cutaneous carcinoma in mice	Cutaneous papillomagenesis↓	Fyn↓ and Nrf2 signal pathway↑ [99,100]
D-limonene	Citrus fruit	DMBA/TPA-induced cutaneous tumor in mice	Cutaneous papillomagenesis↓	Anti-oxidant enzymes↑ [101]
Caffeic acid	Coffee	TPA-induced cutaneous damage in mice	Edema formation↓	MDA↓,GSH↑, anti-oxidant enzymes↑ [102]
DADS	Garlic	DMBA/TPA-induced cutaneous tumor in mice	Cutaneous papillomagenesis↓	p21-dependent Nrf2 signal pathway↑, anti-oxidant enzymes↑ [89]

3.1.2. Epigenetic modulators

Like other solid tumors, cutaneous carcinoma is thought to arise from a series of genetic and epigenetic events. The contribution of epigenetics to the development of cancers has been well supported, involving reversible heritable changes in gene expressions without changing DNA sequences [103]. Due to early incidence and reversible trait during cancer initiation and development, epigenetic modifications play central roles in cancer prevention [61,104]. The main epigenetic mechanisms by which gene expressions are regulated include DNA methylation, chromatin structure alterations by post-translational modification of histones, and miRNAs (Fig. 2). These processes affect DNA folding, transcript stability, chromatin compaction, nucleosome positioning and complete nuclear organization of genetic materials. They synergistically and cooperatively determine gene silencing, as well as the timing and tissue specificity of the expressions of these genes [105,106]. Numerous cutaneous carcinoma pathogens (UVR and chemicals) play pivotal role in silencing multiple gene expression by inducing the modulation of epigenetics, which be another important pathological factor in the initiation of cutaneous carcinoma, such as tumor suppressor genes (TSG) and cytoprotective genes [107-110]. In addition, these epigenetic changes can also potentially serve as molecular biomarkers in tumor tissues and in blood as circulating DNA, for diagnosing cutaneous carcinoma and predicting outcome and progression [265]. Given that epigenetic modification plays an important role in tumorigenesis, dietary phytochemicals which can modulate one or multiple epigenetic changes could be employed as blocking agents for cutaneous carcinoma.

Fig. 2.

Potential molecular targets of epigenetic modulated diet phytochemicals for cutaneous carcinoma chemoprevention.

DNA methylation undergoes catalysis that transfer methyl groups from Sadenosyl-L-methionine to a cytosine adjacent to guanine, known as CpG. Short CpG-rich regions, also known as “CpG islands”, exist in over half of human gene promoters, which are unmethylated in most cases [111,112]. However, enhanced methylation of CpG within gene promoters results in transcriptional silencing of TSG in cancer cells [113,114]. Similar to many solid cancers, both melanoma and NMSC are subjected to changes in DNA methylation of tumor-related genes (e.g. MLH-1, BRCA1 and SOCS1), being closely related with poor prognosis and relapse [115,116]. DNA is also methylated in mouse models of UVB- and DMBA/TPA-induced cutaneous carcinoma [107]. Thus, compounds which can downregulate level of DNA methylation could be considered as efficient candidate drugs for cutaneous carcinoma prevention and treatment. DNA methylation is mainly adjusted by methyltransferases (DNMTs), a family of rate-limiting enzymes. Polypeptides derived from Chlamys farreri was found to prevent carcinogen-induced HaCaT cell transformation through reducing DNMT3b and enhancing the level of tumor suppressor genes p16 and RASSF1A [117]. In addition to DNMTs, Tet family proteins are another key regulators, which can promote DNA demethylation by mediating the main intermediate state: DNA hydroxylation. Vitamin C, an essential nutrient for humans and derived from various fruits and vegetables, was demonstrated to protect cells from UV-induced apoptosis via enhancing Tet1/2-dependent DNA demethylation and re-activating suppressor genes (p16 and p21) eventually [118].

In addition to direct methylation of DNA, post-translational modifications of histone proteins on N-terminal histone tails, including methylation, acetylation, phosphorylation, sumoylation, ubiquitylation and ADP ribosylation, can also influence chromatin structure, playing important roles in tumorigenesis and gene regulation [119]. Most of these modifications occur at arginine, lysine and serine residues within the histone tails and regulate critical cellular processes such as replication, transcription and repair, leading to either repression or activation [120]. Histone modifications in cutaneous carcinoma are usually related to the conversion of normal tissues to neoplastic diseases [121]. Like DNA methylation changes, histone modifications are reversible, which can be regulated by enzymes that covalently modify histone proteins or eliminate such modifications (e.g. HATs and HDACs) [122,123]. Clearly, these enzymes are qualified targets for cancer chemoprevention and prevention. For example, ginsenoside Rg3, a monomer extracted from ginseng, can inhibit melanoma cell A375 and C8161 by decreasing HDAC3 and increasing acetylation of p53 on lysine (k373/k382) both in vitro and in vivo [124].

Additionally, miRNAs are also key moderators of epigenetic genes [125]. Although miRNAs are essential to the physiology of normal cells, aberrant expressions of small non-coding RNAs have been linked to carcinogenesis [126-128]. In cutaneous carcinoma, miRNAs, including miR-214, miR-30b, miR-506, miR-21, miR-31 and miR-221 as oncogenes together with miR-137, miR-29c, miR-205, miR034b and miR-375 as tumor suppressors, significantly affect the process of tumorigenesis [129,130]. In short, miRNAs have regulatory effects on key signaling pathways in almost the whole process of cutaneous carcinoma, so particular attention should be paid to miRNA-based cancer prevention and treatment [131]. Curcumin, polyphenol derived from curcuma longa, was found to block tumorigenicity and growth of B78H1 cells mainly through enhancing miR-205-5p level which effecting on cell proliferation and apoptosis eventually [132].

Moreover, interestingly, most of dietary phytochemicals are able to reverse multiple epigenetic changes in a systematic and comprehensive manner and then prevent the initiation and development of cutaneous carcinoma, such as EGCG, proanthocyanidins and apigenin. EGCG, an active and major constituent of green tea, has been shown to have both preventive and therapeutic effect on cutaneous carcinoma through multiple epigenetic modifying and eventually re-expressing tumor suppressor genes, p 16INK4a and Cip1/p21. This compound can not only decrease DNA methylation mediated by inhibiting level and activity of DNMT1, DNMT3a and DNMT3b, but also enhance levels of acetylated lysine 9 and 14 on histone H3 (H3-Lys 9 and 14) and lysine 5, 12 and 16 on histone H4 via decreasing HDAC activity. Besides, this compound can also inhibit levels of trimethylated lysine 27 on histone H3 [133-135]. Table 2 and Fig. 2 show representative dietary agents which have been demonstrated as blocking agents for cutaneous carcinoma through regulating major epigenetic modification mentioned above.

Table 2.

Cutaneous carcinoma-specific epigenetic alteration and related protein expression/activity regulated by some chemopreventive diet phytochemicals.

Phytochemicals	Origin	Cell or animal models	Effect	Mechanism
EGCG	Green tea	UV-induced photo-carcinogenesis in mice	Cutaneous papillomagenesis↓	UVB-induced global DNA hypomethylation pattern↓ [133]
		SCC-13 Cutaneous carcinoma cell in vitro	Cell apoptosis↑	TSG (Cip1/p21)↑, Histone methylation↓ and acetylation↑, PcG protein↓ (Ezh2 and Bmi-1) [134]
		A431 cutaneous carcinoma cell in vitro	Cell survive↓	TSG (Cip1/p21 and p16ink4a)↑, DNA methylation↓, histones acetylation↑, DNMT1, DNMT3a and DNMT3b↓, HDAC↓ [135]
Sulforaphane	Broccoli; cabbage; cauliflower; kale	TPA-induced JB6P+ cell transformation	Grade malignancy↓	Nrf2↑, DNA methylation↓, histones acetylation↑, DNMT1, DNMT3a and DNMT3b↓, HDACs↓ [136]
		SCC-13 Cutaneous carcinoma cell in vitro	Cell cycle arrest↑, cell apoptosis↑	TSG (Cip1/p21)↑, Histone methylation↓ and acetylation↑, PcG protein↓ (Ezh2 and Bmi-1) [137]poptosis of skin cancer cell through
Curcumin	Turmeric	B78H1-tumor-bearing C57BL/6 mouse models	Tumor growth↓	Anti-apoptosis (Bcl-2) and pro-proliferation protein (PCNA)↓, miR-205-5p↑ [132]
Proanthocyanidins	Grape seed	A431 and SCC13 cutaneous carcinoma cell in vitro	Cell survival↓	TSG (RASSF1A, p16 and Cip1/p21)↑, DNA methylation↓, histones acetylation↑ and histones methylation↓, DNMT1, DNMT3a and DNMT3b↓, HDACs↓, HAT↑ [138]
Kaempferol	Tea, broccoli, grapes, apples	UV-induced photo-carcinogenesis in mice	Cutaneous papillomagenesis↓	AP-1 and NF-κB↓, histone H3 phosphorylation↓, RSK2 and MSK1↓ [139]
Polypeptides	Chlamys farreri	UVB- induced HaCaT cell transformation	Grade malignancy↓	TSG (p16 and RASSF1A)↑, DNA methylation↓, DNMT1, DNMT3a, DNMT3b↓ [117]
Apigenin	Caraway	Mouse cutaneous epidermal JB6 P+ cells in vitro	Not mentioned	Nrf2↑, DNA methylation↓, histones acetylation↑, DNMT1, DNMT3a and DNMT3b↓, HDACs↓ [140]
Ginsenoside Rg3	Ginseng	A375 and C8161 Cutaneous carcinoma cell in vitro	Cell cycle arrest↑	p53↑, histones acetylation↑, HDAC3↓ [124]
Butyric acid, nicotinamide and calcium glucarate	Dairy products	DMBA induced cutaneous carcinoma in mice	Cutaneous papillomagenesis↓	TSG (p16)↑, tumor suppressor (miR203)↑, DNA methylation↓, histones acetylation↑, DNMT1↓ and HDAC1↓ [141]
Vitamin C	Vegetables and fruits	UV-induced cell photodamage	Cell apoptosis↓	TSG (p21 and p16)↑, Tet1/2-dependent DNA demethylation↑ [118]

3.2. Cutaneous carcinoma chemopreventive phytochemicals as suppressing agents

Compounds that influence later stages (promotion and progression) of carcinogenesis are referred to as “suppressing agents” for being able to decrease the proliferative capacity of initiated cells [142]. They prevent the cutaneous tissue chronic inflammation and proliferation of pre-malignant cells by down-regulating signal transduction pathways such as STAT3 and NF-κB [143-145]. Additionally, suppressing agents may also prevent or delay malignant cancer cells from metastasis by inhibiting pathways inducing angiogenesis, epithelial mesenchymal transition, invasion and dissemination which are mainly responsible for cancer-related death [146,147].

3.2.1. Anti-inflammation activity

“Chronic inflammation”, as suggested by epidemiological and experimental evidences, can be induced by mechanical injuries, physical agents (UVR), chemical agents (arsenic, tar products and immune-modulatory drugs), biological agents (parasites, viruses, bacteria and fungi) and immunological disorders (autoimmunity, hypersensitivity reactions and immune deficiency states) [148]. Accordingly, it is one of the hallmarks of environmental agent-mediated cutaneous carcinomas that affect almost all the important aspects (e.g. survival of cancer cells, responses to hormones and chemotherapeutic drugs, metastasis and angiogenesis) [149,150]. In clinical practice, such pathological phenomenon (e.g. chronic wound sites and dystrophic epidermolysis bullosa) may predispose individuals to augment susceptibility of cutaneous carcinoma [151]. Considering the potential role of inflammation in tumor initiation and its dominant role in promotion/progression, angiogenesis and metastasis, the inflammation-related pathways and factors mentioned above may be attractive targets for the prevention and treatment of cutaneous carcinoma [152,153]. Interestingly, long-term use of aspirin, a traditional non-steroidal anti-inflammatory drugs, has shown obvious chemopreventive effects on cutaneous carcinoma in epidemiological and clinical studies [154].

The pathways connecting cancer and inflammation are either intrinsic or extrinsic [155]. Intrinsic pathways are initiated by genetic events, involving inactivation of tumor suppressor genes (p16/INKA4 and p14/ARF) and activation of oncogenes (H-ras, N-ras and c-myc) by mutation, amplification or chromosomal rearrangement [156]. In contrast, extrinsic pathways represent soluble mediators and inflammatory leukocytes caused by mechanical, UVR, ROS, ionizing radiation and skin-related microorganisms (e.g. Neisseria gonorrhoeae, Borrelia burgdorferi, Staphylococcus aureus, measles virus and HIV-1). Moreover, some extrinsic factors also frequently affect gene products such as MC1R and MITF [157-159]. As a result, cooperation between these two pathways stimulates multiple transcription factors (mainly NF-κB, STAT3 and AP-1) in cutaneous cell through activating intracellular kinase system (MAPK, PI3K/Akt, JAK), and then a cancer-related inflammatory microenvironment forms, accompanied by elevated risks of cutaneous carcinoma development and aggravation. Thus, dietary products that can modulate these three transcription factors, which can coordinate the transcription of hundreds of target genes, are generally treated as suppressing agents for cutaneous carcinoma.

Genes for various chemokines (IL-6, IL-1 and TNF), cytokines, VCAM-1, intercellular adhesion molecule-1, E-selectin and urokinase plasminogen activator are essential to the initiation and deterioration of cutaneous inflammation. Geraniol was found to protect cutaneous tissue from TPA-induced damage through downregulating level of multiple chemokines (IL-6, IL-1 and TNF) via inactivating p38-dependent NF-κB [160]. They can also regulate pro-inflammatory enzymes (e.g. COX-2 and iNOS) that participate in chronic inflammation of the skin and subsequently in carcinogenesis. Pterostilbene, a natural analogue of resveratrol from blueberries, was found to prevent DMBA/TPA-induced cutaneous inflammation (iNOS and COX-2) and papillomas through restraining NF-κB and AP-1 via inactivating MAPK and PI3K/Akt [161]. In our lab, we have demonstrated menthol can protect cutaneous tissue from chemical carcinogens via its anti-inflammatory ability by downregulating p38 and ERK-dependent NF-κB pathway [162]. Additionally, these three transcription factors can modulate the expressions of genes controlling cancer cell apoptosis (Bcl-2, Bcl-xL, c-FLIP, XIAP and survivin), proliferation (c-Myc and cyclins), angiogenesis (VEGF), and metastasis (MMPs) [163]. Topical application of honokiol, an active constituent of Magnolia plant, resulted in the prevention of UVB-induced cutaneous papilloma formation through inhibiting proinflammatory disorder (IL-6, IL-1, TNF, COX-2 and PGE2) and cell proliferation (PCNA, cyclin D1, D2, E and CDKs) via inactivating PI3K/Akt [164].

In daily meals, there are various dietary products that can modulate one or multiple signaling pathway (NF-κB, STAT3 and AP-1) and have outstanding, broad-spectrum anti-inflammatory activities, accompanied by chemopreventive proficiency in laboratory models in vivo and in vitro (Table 3 and Fig. 3). Being further associated with lower cutaneous carcinoma risks in human studies, such functional agents may be eligible candidates for development like aspirin.

Table 3.

Cutaneous carcinoma-specific inflammatory condition and related protein expression/activity regulated by some chemopreventive diet phytochemicals.

Phytochemicals	Origin	Cell or animal models	Effect	Mechanism
EGCG	Green tea	UV-induced photo-carcinogenesis in mice	Cutaneous papillomagenesis↓	Pro-inflammatory cytokines↓, COX-2↓, PGE2↓, PCNA↓, and cyclin D1↓ [165]
Polyphenols	Black tea	DMBA/TPA-induced cutaneous tumor in mice	Cutaneous papillomagenesis↓	COX-2↓ through MAPK↓, AP-1↓ and NF-κB↓ [166]
Resveratrol	Red grape	DMBA/TPA-induced cutaneous tumor in mice	Cutaneous papillomagenesis↓	COX-2↓, IL-6↓, AP-1↓ and NF-κB↓ [167]
Pterostilbene	Blueberry	DMBA/TPA-induced cutaneous tumor in mice	Cutaneous papillomagenesis↓	COX-2↓, iNOS↓, MAPK↓, AP-1↓ and NF-κB↓ [161]
Silymarin	Milk thistle	UV-induced photo-carcinogenesis in mice	Cutaneous papillomagenesis↓	COX-2↓, iNOS↓, STAT3↓ and NF-κB↓ [168]
Rosmarinic acid	Rosemary	DMBA/TPA-induced cutaneous tumor in mice	Cutaneous papillomagenesis↓	PGE2↓, COX-2↓, chemokines KC↓, macrophage inflammatory protein-2↓ [169]
Bromelain	Pineapple	DMBA/TPA-induced cutaneous tumor in mice	Cutaneous papillomagenesis↓	COX-2↓, NF-κB↓, MAPK↓, Akt↓ [170]
Oligonol	Lichee	DMBA/TPA-induced cutaneous tumor in mice	Cutaneous papillomagenesis↓	COX-2↓, NF-κB↓, MAPK↓ [171]
D-limonene	Citrus fruit	DMBA/TPA-induced cutaneous tumor in mice	Cutaneous papillomagenesis↓	Cutaneous inflammation↓, COX-2↓ [101]
Diallyl trisulfide (DATS)	Garlic	DMBA/TPA-induced cutaneous tumor in mice	Cutaneous papillomagenesis↓	COX-2↓, iNOS↓, Akt↓, JNK↓, AP-1↓ [172]
CF-TP	Pinnatifida	TPA-induced JB6P+ cell transformation	Grade malignancy↓	COX-2↓, iNOS↓, NF-κB↓, AP-1↓ [173]
		DMBA/TPA-induced cutaneous tumor in mice	Cutaneous papillomagenesis↓
Apigenin	Caraway	UVB-induced cutaneous photodamage in mice and in JB6 P+ cell	Inflammatory response↓	COX-2↓, Src↓ [174]
Geraniol	Rose	TPA-induced cutaneous damage in mice	Inflammatory response↓	NF-κB↓, p38↓, TNF-α↓, IL-1β↓, and IL-6↓ [160]
Honokiol	Magnolia officinalis	UV-induced photo-carcinogenesis in mice	Cutaneous papillomagenesis↓	COX-2↓, PGE2↓, PCNA↓, cyclin Ds↓, CDKs↓, pro-inflammatory cytokines↓ [164]
Delphinidin	Berry	TPA-induced JB6P+ cell transformation	Grade malignancy↓	COX-2↓, PGE2↓, NF-κB↓, AP-1↓ through MEK/ERK↓ [175]
Menthol	Mint	DMBA/TPA-induced cutaneous tumor in mice	Cutaneous papillomagenesis↓	COX-2↓, NF-κB↓, ROS↓ [162]
Dehydroglyasperin C	Licorice	TPA-induced JB6P+ cell transformation	Grade malignancy↓	COX-2↓, NF-κB↓, AP-1↓ through MKK4↓ and PI3K↓ [176]
Momordica grosvenori extract	Momordica grosvenori	DMBA/TPA-induced cutaneous tumor in mice	Cutaneous papillomagenesis↓	COX-2↓, iNOS↓, NF-κB↓, MAPK↓, Akt↓ [177]
Berteroin	Cruciferous vegetables	TPA-induced cutaneous damage in mice	Edema formation↓	COX-2↓, iNOS↓, NF-κB↓, TNF-α↓, IL-6↓, IL-1β↓, Akt↓, ERK↓ [178]
Hexahydro-beta-acids	Lupulus	DMBA/TPA-induced cutaneous tumor in mice	Cutaneous papillomagenesis↓	COX-2↓, iNOS↓, MAPK↓, Akt↓, NF-κB↓ [179]
Flavonoid	Artocarpus communis	DMBA/TPA-induced cutaneous tumor in mice	Cutaneous papillomagenesis↓	COX-2↓, PGE2↓, MAPK↓, Akt↓, NF-κB↓, –AP-1↓, pro-inflammatory cytokines↓ [180]
Phloretin	Apple	DMBA/TPA-induced cutaneous tumor in mice	Cutaneous papillomagenesis↓	COX-2↓, NF-κB↓, ERK↓ [181]
Phenethyl isothiocyanate	Cruciferous vegetables	TPA-induced cutaneous damage in mice	Edema formation↓	COX-2↓, iNOS↓, NF-κB↓, ERK↓, Akt↓, TNF-α↓, IL-6↓, IL-1β↓ [182]
6-shogaol	Ginger	DMBA/TPA-induced cutaneous tumor in mice	Cutaneous papillomagenesis↓	COX-2↓, iNOS↓, NF-κB↓, MAPK↓, Akt↓ AP-1↓ [183]
Caffeic acid	Coffee	TPA-induced cutaneous damage in mice	Edema formation↓	COX-2↓, NF-κB↓, TNF-α↓ [102]

Fig. 3.

Potential molecular targets of anti-inflammatory diet phytochemicals for cutaneous carcinoma chemoprevention.

3.2.2. Anti-angiogenesis activity

Pathological angiogenesis, which is regarded as unregulated angiogenesis typically, mainly drives many serious human diseases including cancers [184]. Since angiogenesis delivers nutrients and oxygen to growing tumors, it is an essential pathological feature of cancer, also playing vital roles in enabling other aspects of tumor pathology such as dissemination/metastasis and metabolic deregulation [185,186].

Cancers occurring in the skin, like all solid malignancies, are also highly angiogenic, including benign growth [187,188]. For instance, warts have increasing vascularity that is accompanied with growth and persistence [189]. UVR and chemical carcinogen play vital roles in vascularization-related cutaneous lesion. In normal cutaneous tissues, however, acute damage drastically changes the levels of growth factors and cytokines [190,191]. Angiogenesis stimulators, such as FGF and VEGF, are significantly up-regulated, thus increasing the cutaneous microvessel density. In the meantime, endogenous angiogenesis inhibitors, such as TSP-1, are significantly locally reduced. As mentioned above, carcinogen-induced chronic damage can cause the accumulation of cutaneous tissue mutations, probably leading to neoplastic and hyperplastic transformations. Hyperplastic cutaneous lesions, including atypical melanocytic nevi and AKs, have higher capillary densities than those of surrounding normal tissues [192]. This situation is more obvious during the promotion from hyperplasia to neoplasia (e.g. BCC and SCC) and the progression to malignant melanoma, with higher levels of angiogenesis mediators including FGF-2, VEGF, PIGF, IL-8, MMPs and Ang-2 [193-196]. Above all, angiogenesis is necessarily involved throughout cutaneous carcinoma, especially in promotion and progression, as an available pathological process for preventing cutaneous carcinoma.

The anti-angiogenic properties of many dietary phytochemicals against cutaneous carcinoma have been evaluated in vivo and in vitro. The main mechanisms underlying their anti-angiogenic effects include: (1) inhibition of MMPs: MMPs, a series of zinc-containing endopeptidases, can cleave a wide range of ECM components, promote activated endothelial cells development and invasion. Furthermore, MMPS also play a primary role in angiogenesis by promoting the expression of VEGF, mediating endothelial cell migration and vascular formation processes [197]. Topical application of EGCG, an active constituent of green tea, resulted in the prevention of UV-induced cutaneous papilloma formation partly through inhibiting tumor angiogenesis by decreasing level of MMP-2, MMP-9 and VEGF. (2) modulation of angiogenic related signaling pathways: NF-κB, HIF-1α and AP-1 are the most vital transcription factors in cancer cells, which can control the expression of multiple angiogenesis-related proteins, such as COX-2, growth factors and cytokines [198,199]. These substances cannot only degrade the extracellular matrix, but also activate various growth factor receptors, which can promote the survival, proliferation, metastasis of these tumor endothelial cells and capillary sprout formation. Antiangiogenic activity of berberine in B16F10 xenograft tumor is mediated through the downregulation of HIF1, NF-κB, VEGF, and proinflammatory mediators (ILs, COX-2, iNOS TNF-α) [200]. Most of dietary phytochemicals are able to reverse both two mechanisms mentioned above and then prevent the cutaneous carcinoma angiogenesis and tumor growth. β-carotene has been demonstrated inhibit melanoma inflammatory angiogenesis through decreasing level of serum cytokine (IL-1, IL-6, TNF and GM-CSF), MMP-2, MMP-9 and inactivating NF-κB and AP-1 [201]. Fig. 4 and Table 4 conclude representative cutaneous carcinoma chemopreventive dietary agents capable of blocking tumor angiogenesis and delaying cutaneous carcinoma promotion and progression.

Fig. 4.

Potential molecular targets of anti-angiogenic diet phytochemicals for cutaneous carcinoma chemoprevention.

Table 4.

Cutaneous carcinoma-specific excessive angiogenesis and related protein expression/activity regulated by some chemopreventive diet phytochemicals.

Phytochemicals	Origin	Cell or animal models	Effect	Mechanism
EGCG	Green tea	UV-induced photo-carcinogenesis in mice	Cutaneous papillomagenesis↓	Cutaneous carcinoma vascular↓ through VEGF↓, MMP-2↓ and MMP-9↓ [202]
Resveratrol	Red grape	DMBA-induced cutaneous tumor in mice	Cutaneous papillomagenesis↓	Cutaneous carcinoma vascular↓ through VEGF↓, MMP-2↓ and MMP-9↓ in TLR4-dependent manner [203]
Apigenin	Caraway	UV-induced cutaneous photodamage in mice	Epidermal thickness↓, keratinocyte layers↓	Microvascular density (MVD) in the dermis↓, TSP1↑, VEGF↓, COX-2↓ [204]
Myricetin	Waxberry	UV-induced photo-carcinogenesis in mice	Neovascularization in cutaneous↓	HIF-1↓, VEGF↓, MMP-2↓, MMP-9↓, PI3K/Akt↓ [205]
Betulin	Raisins	DMBA/TPA- induced cutaneous tumor in mice	Cutaneous papillomagenesis↓	Tumor angiogenesis↓, VEGF↓ [206]
β-carotene	Green leafy vegetables and orange fruits	B16F10-tumor-bearing mouse models	Tumor growth↓	Inflammatory angiogenesis↓, serum cytokine levels↓, MMP-2↓, MMP-9↓, TIMP-1↑ by NF-κB↓ and AP-1↓ [201]
Ascorbic Acid	Vegetables and fruits	A2058-tumor bearing athymic nude mouse model	Tumor growth↓	Tumor angiogenesis↓ by VEGF↓ and MMP-9↓ [207]
Tocopherol	Vegetable oil, nut	B16F10-tumor bearing mouse models	Tumor growth↓	Tumor angiogenesis↓ by VEGF↓, VEGFR1↓ and VEGFR2↓ [208]
Berberine	Coptis chinensis	B16F10-tumor-bearing mouse models	Neovascularization in melanoma↓	Pro-angiogenic factors↓ (such as HIF, VEGF, COX-2, NO, NF-κb, and proinflammatory cytokines) [200]
Genistein	Soybean	B16-tumor-bearing mouse models	Tumour blood supply↓	Not mentioned [209]
13-cis-Retinoic acid	Animal foods, carrot, tomato	B16F10-tumor-bearing mouse models	Tumor directed capillaries↓	Proinflammatory cytokines↓, VEGF↓, TIMP-1↑, NF-κb↓ and AP-1↓ [210]

3.2.3. Anti-migration activity

Melanoma accounts for merely 4% of all cutaneous carcinoma cases, but it is highly metastatic and most aggressive, causing about 80% of all related deaths [211]. As other metastatic tumors, melanoma cells progress from benign melanocyte hyperplasia into metastatic melanoma by undergoing a remarkable cascade of events. The process of metastasis consists of two steps [212]. Firstly, melanoma cells move and leave their primary sites through multiple courses from extension, adhesion, contraction to detachment. Secondly, melanoma cells that complete the first step are allowed to enter lymphatic or blood vessels (intravasation) and then target organs (extravasation) [213,214]. Given that melanoma therapy is greatly challenged by the metastatic properties of malignant cells, blocking their migratory and invasive capacities by using phytochemicals may pave the way for the prevention and treatment of cutaneous carcinoma (melanoma). Most related studies mainly focuses on the first step that is orchestrated by several external factors and signaling pathways, including proteases, chemokines, growth factors/receptors, extracellular matrix proteins, matrix-degrading enzymes, integrins, cell–cell communication proteins and cell–cell adhesion molecules [215].

First, the migration of melanoma cells begins with the extension of lamellipodium, after escaping the control keratinocytes. Stimulated and regulated by Rac protein, which is overactive in most metastatic melanoma cells, is underpinned by polymerization of actin that provides a traction force for pushing the membrane to move [216]. Capsaicin, the major pungent ingredient of red pepper, has been reported inhibits the migration of B16F10 cells through inhibiting Rac activity by inactivating PI3K/Akt signal pathway [217]. Afterwards, the extended lamellipodium needs to anchor the ECM through adhesion molecules to facilitate cell attachment and spreading [216,218,219]. Oral administration of ursolic acid increased the survival rate of melanoma lung metastasis in C57BL/6 mice through inhibiting focal adhesion signaling pathway, including ICAM-1, VCAM-1, E-selectin, integrin α6β1, etc [220]. Then, to penetrate the matrix, surface proteases, such as MMPs, are recruited toward the attachment sites to hydrolyze adjoining ECM substrates. In invasive melanoma cases, MMP-9, MMP-2 and MT1-MMP are especially up-regulated [221,222]. The regulation of MMPs depends on mutiple intracellular signal transduction processes, such as nuclear transcription factors (e.g. NF-κB, AP-1, ATF-2 and HIF), signaling pathways (e.g. Ras/PI3K/Akt) and inflammatory disorder (e.g. COX-2, EP2, IL-6, IL-1β, TNF-α and GM-CSF) [223,224]. Carnosol, a constant constituent of Rosmarinus, was found to block B16F10 cell invasion by reducing MMP-9 expression and activity through suppressing MAPK and Akt signaling pathway and inhibition of NF-kappaB and AP-1 binding activity [225]. Finally, the trailing edge of cells is detached from ECM and cells now are free to keep moving forward eventually leaving the tumour primary site [212]. We herein reviewed the diet chemical entities with well-documented in vitro and in vivo effects on melanoma migration (Table 5 and Fig. 5).

Table 5.

Chemopreventive diet phytochemicals regulate melanoma metastasis and related protein expression/activity.

Phytochemicals	Origin	Cell or animal models	Effect	Mechanism
Berberine	Coptis chinensis	A375 and Hs294 in vitro	Cell invasion↓, TPA-induced cell migration↓	COX-2↓, PGE2↓, EP2↓, EP4↓, NF-κb↓ [226]
		A375 and B16F10 in vitro, B16F10 experimental pulmonary metastasis in mice	Cell invasion and migration↓, lung metastasis↓	AMPK↑, ERK↓, COX-2↓ [227]
Proanthocyanidins (PC)	Grape	A375 and Hs294t in vitro, TPA-stimulated A375 in vitro, A375 experimental pulmonary metastasis in mice	Cell invasion and migration↓, lung metastasis↓	COX-2↓, EP2↓, EP4↓, NF-κb↓, epithelial biomarkers↑ (E-cadherin, cytokeratin), mesenchymal biomarkers↓ (vimentin, fibronectin and N-cadherin) [228]
Anthocyanins	Mulberry	B16F1 in vitro, B16F1 spontaneous metastatic model in mice	Cell invasion and migration↓, lung and liver metastasis↓	MMP-2/9↓, Ras↓, Akt↓, NF-κb↓ [229]
Silymarin	Milk thistle	A375 and Hs294t in vitro	Cell invasion and migration↓	β-catenin↓, MMPs↓ [230]
Quercetin	Fennel, caraway, onion	HGF-stimulated A2058 and A375 in vitro	Cell invasion and migration↓	C-Met↓, Gab1↓, FAK↓, PAK↓ [231]
		A375 and A2058 in vitro, B16F10 experimental pulmonary metastasis in mice	Cell invasion and migration↓, lung metastasis↓	STAT3↓, MMP-2↓, MMP-9↓, VEGF↓ [232]
Apigenin	Caraway	B16F10 experimental pulmonary metastasis in mice	Lung metastasis↓	STAT3↓, MMP-2↓, MMP-9↓, VEGF↓ and Twist1↓ [233]
EGCG	Green tea	A375 and Hs294t in vitro	Cell invasion and migration↓	COX-2↓, PGE2↓, EP2↓, EP4↓, epithelial biomarkers↑ (E-cadherin, cytokeratin and desmoglein 2), mesenchymal biomarkers↓ (vimentin, fibronectin and N-cadherin) [234]
		M17 in vitro	Cell migration↓	MMP-2↓, TIMP-2↑, ERk↓ [235]
Capsaicin	Pepper	B16F10 in vitro	Cell migration↓	Akt↓, PI3K↓, Rac1↓ [217]
Resveratrol	Red grape	B16F10 in vitro, B16BL6 experimental pulmonary metastasis in mice	Cell invasion and migration↓, lung metastasis↓	Akt↓ [236]
Pterostilbene	Blueberry	B16MF10 experimental liver metastasis in mice	Metastatic growth to the liver↓	Vascular adhesion molecule 1↓ [237]
Gallic acid	Grape, tea	A375. S2 in vitro	Cell invasion and migration↓	Ras/ERK pathway↓, pathways MMP-2/9↓ [238]
Riboflavin	Animal foods, carrot, tomato	B16F10 in vitro, B16F10 experimental pulmonary metastasis in mice	Cell invasion and migration↓, lung metastasis↓	TIMP↑, MMPs↓, HH pathway↓ [239]
Carnosol	Rosemary	B16F10 in vitro	Cell invasion↓	MMP↓, Akt↓, MAPK↓ NF-κb↓, AP-1↓ [225]
Parthenolide	Feverfew	A375 and WM793 in vitro	Cell invasion and migration↓	NF-κb↓, IL-8↓ and MMP-9↓ [240]
Lipid-soluble extract	Ginseng	B16F10 in vitro, B16F10 experimental pulmonary metastasis in mice	Cell migration↓, lung metastasis↓	MMP-2↓ [241]
Ginsenoside Rg3	Ginseng	B16F10 in vitro	Cell invasion and migration↓	MMP-13↓ [242]
1-Deoxynojirimycin ursolic acid	Mulberry Berries	B16F10 in vitro B16F10 experimental pulmonary metastasis in mice	Cell invasion and migration↓ lung metastasis↓	MMP-2/9↓, TIMP↑, α-mannose↑ [243] focal adhesion pathway (ICAM-1, VCAM-1, E-selectin, P-selectin, integrins)↓ [220]

Fig. 5.

Potential molecular targets of anti-migratory diet phytochemicals for cutaneous carcinoma chemoprevention.

4. Cutaneous carcinoma chemoprevention using dietary phytochemicals: clinical studies

Although the preventive effects of diverse bioactive phytochemical constituents on cutaneous carcinogenesis have been well-documented, their efficacy, safety and dose adjustment for human remain largely unknown. It is crucial to develop cutaneous chemoprotective or chemopreventive agents based on natural compounds by translating these preclinical findings into clinical settings. Some well-defined chemopreventive phytochemicals (curcumin, green tea polyphenols, sulforaphane and resveratrol) have been verified to affect various biological activities such as inactivation of protein kinases (PI3K/Akt and MAPK), modulation of the activities of transcriptional factors (AP-1, NF-κB, STAT3 and Nrf2), decrease of inflammatory and growth factors (TNF-α, VEGF and IL-1β) and regulation of epigenetic alterations (HDACs and DNMTs). Accordingly, multi-stages of cutaneous cell cancerization and deterioration may be better inhibited by such versatile chemicals via modulating key cellular proteins participating in different signaling transduction pathways and thus changing the expressions of genes involved in epigenetic modification, antioxidation and cancer-related angiogenesis and inflammation. Up to now, human intervention trials that target cutaneous carcinoma prevention are still lacking, cutaneous damages and diseases have been treated by these versatile chemicals though. As indicated by the limited human trials, systemic administration of these phytochemicals has protective benefits, barely causing adverse effects also.

4.1. Green tea polyphenols

Polyphenols derived from green tea, also known as green tea polyphenols (GTPs), have attracted global attention recently because of beneficial effects, especially significant roles in cancer chemoprevention and chemotherapy. GTPs predominantly comprise (−)-epigallocatechin, (−)-epigallocatechin-3-gallate (EGCG), (−)-epicatechin and (−)-epicatechin-3-gallate, among which EGCG is most abundant and associated with the majority of green tea intake-related health benefits [21]. Although GTPs have been widely proven as promising chemopreventive agents in preclinical studies, their clinical benefits for human subjects remain elusive. As a comprehensive and noninvasive biomarker for evaluating UV radiation (UVR) damage, erythema has been used as a quantifiable surrogate end point for cutaneous damage and risk of cutaneous carcinoma [244]. Topical application of GTPs can reduce the number of sunburnt cells, photoprotect against UVR-induced erythema response and DNA damage, and protect epidermal Langerhans cells [245]. Similarly, Heinrich U et al. validated the photoprotective bioactivities of orally administered polyphenols in a 12-week, double-blinded, placebo-controlled study [246]. In a phase I clinical study, topical use of 660 μM EGCG for two weeks during radiotherapy was non-toxic for patients with non-inflammatory breast cancer, which managed to prevent radiation-induced dermatitis effectively and to lower the symptom scores of burning, pain, tenderness and itching significantly [247]. Therefore, GTPs/EGCG can relieve carcinogen-induced cutaneous damages and may then help prevent cutaneous carcinogenesis. In-depth studies are still in need to further demonstrate the relationships between these compounds and cutaneous cancer or precancerous lesions.

4.2. Curcumin

As a component of turmeric, curcumin is a strong antioxidant and anti-inflammatory agent and has been employed to treat cutaneous ailments such as acne, scabies, wound, eczema and wrinkled skin. Due to low toxicity and broad-spectrum applications, curcumin has been extensively studied, including in cancer prevention and treatment. In a phase I clinical trial of Chen et al., curcumin that was orally taken at up to 8 g/day for 3 months was non-toxic to human and improved the histological characteristics of arsenic Bowen’s disease of the skin, one of the main precancerous symptoms [248]. To exert pharmacological effects on tissues by augmenting the absorption and bioavailability of curcumin, several formulation techniques, such as combination with a naturally bioavailable enhancer (curcumin C3 complex combining curcumin with piperine), have been developed [249]. A randomized, double-blinded, placebo-controlled clinical trial demonstrated that oral administration of curcumin C3 complex (equivalent to 2 g curcumin) three times a day effectively prevented radiation-induced dermatitis during radiotherapy for breast cancer [250]. Additionally, continuously using this formulation for 4 weeks also enhanced the activities of various antioxidant enzymes, and alleviated sulfur mustard-induced atopic dermatitis and cutaneous pruritus [251]. Moreover, some percutaneous absorption preparations for topical administration, such as curcumin cream [252], have been developed to maintain a biologically effective concentration in cutaneous tissues. Thus, given either systemically or topically, curcumin can change the cutaneous biochemistry in human body and prevent cutaneous carcinogenesis.

4.3. Sulforaphane

Sulforaphane, naturally occurring in cruciferous vegetables such as broccoli and cabbage, has been highlighted recently. Preclinical studies have verified that it inhibited tumor development and progression by preventing inflammation, oxidative stress and carcinogenesis. Still, the cancer preventive effects of sulforaphane on human have not yet been well validated. A randomized, double-blinded, and placebo-controlled study demonstrated that topical application of sulforaphane-containing extracts (200 nmol/cm², 3 times/day) protected healthy human subjects against development of cutaneous erythema induced by solar-simulated UVR through activation of the Nrf2 signaling pathway [253]. Likewise, Talalay et al. found that after topical application of sulforaphane-rich extracts from 3-day-old broccoli sprouts, phase 2 enzyme (NQO1) in the homogenates of human cutaneous punch biopsies with 3-mm full thickness was up-regulated, and the susceptibility to erythema resulting from narrow-band (311 nm) UVR was attenuated, without any adverse reactions [254]. Additionally, sulforaphane (5 and 10 μM) can alleviate UVR-induced structural damages in sunburnt cells and apoptosis by activating the Nrf2 pathway and raising the levels of several antioxidant enzymes (CAT, HO-1, NQO1 and γGCS) in the full-thickness skin explant samples collected from patients receiving abdominoplastic surgery [92]. Since all the studies focused only on whether sulforaphane protected cutaneous tissues from carcinogen (UVR)-induced damages hitherto, the applicability of this compound to cutaneous cancer prevention in human body still needs further research.

4.4. Resveratrol

With well-established effects on inflammation, oxidative stress, angiogenesis and metastasis, resveratrol has become a feasible chemopreventive agent for cutaneous carcinoma, but its clinical benefits for human remain unclear. Topically applying a formulation containing 1% resveratrol, 0.5% baicalin and 1% vitamin E for 12 weeks can mildly modulate photodamaged skin, thereby being suitable for cutaneous rejuvenation [255]. Given the low bioavailability of this compound when administrated either orally or topically, novel formulation strategies have been attempted. For example, topically treating human volunteers with resveratrol-containing cream improved skin-related parameters including sharply decreased aging signs [256]. Researchers have endeavored to realize dermal resveratrol delivery into human skin by using formulation techniques such as optimized microemulsions [257] and lipid-core nanocapsules [258]. In addition, Amiot MJ et al. developed a soluble resveratrol formulation that had an 8.8-fold higher plasma concentration in healthy volunteers than that of powders [259]. Based on these pharmaceutical achievements in human subjects, it is necessary to further confirm the chemopreventive activities of resveratrol against cutaneous carcinoma.

4.5. Apigenin

As a flavone, apigenin has shown antioxidant, anti-inflammatory and anti-angiogenic effects in experimental studies, being closely associated with its prevention properties against cutaneous carcinoma. However, developing apigenin for clinical use is also obstructed by its low permeability and bioavailability. The concentration of apigenin in cutaneous tissues has been tentatively elevated by liposomes, etc. Topically applying liposomal creams containing apigenin can effectively reverse the inflammatory state in patients suffering from contact dermatitis [260]. A similar formulation is also capable of suppressing UV-induced cytotoxicity and preventing skin aging signs in clinical practice [261]. Hence, apigenin has outstanding biological activities and clinical efficacy, allowing it a potential cutaneous carcinoma-preventive compound, which, however, needs to be further validated.

5. Conclusion and future prospects

The incidence and death rates of cutaneous carcinoma have skyrocketed compared with those of other cancers in recent years. Even if effective cutaneous carcinoma treatment modalities (including chemo-, radio-, photodynamic-, immunotherapies and selective inhibitors) have been developed, the burden of cutaneous carcinoma remains chronically high as their potential treatment-resistant and serious toxic effect. The upgraded efficacy of treatment commonly arises with the potential expense of toxicity, which depending on the specific agents used as adjuvants, as well as on the dose used, the extent of treatment and the route of administration [10,11]. As an example, BRAF inhibitors show ability as a potentially effective treatment in BRAFV600 mutated metastatic melanoma patients. However, major limitations include an dermatological “off target” effects and serious adverse reactions, as numerous cutaneous toxicities [263].

Nowadays, chemoprevention by using edible diet phytochemicals has become an inexpensive, easily applicable, accessible and acceptable approach to control and to manage cutaneous carcinoma. With healthcare costs being a key issue, consumption of phytochemicals would be a more cost-effective cancer-preventive strategy than use of clinical drugs. These compounds may not be so effective as chemotherapeutic or pharmaceutical agents, but they have clear potentials. Furthermore, diet phytochemicals may play exciting roles in preventive care, especially because they only need to be supplemented in the daily diet and lifestyle regimens with skyscraping safety and wide human acceptance in a relative long-term use process. Phytochemicals have lower specificities to single target proteins than synthetic inhibitors do, which may reduce the toxicities of the former. In addition, as the speciality of a native compound, each one of them has versatile multproperties (e.g. anti-inflammation, antioxidation, anti-metastasis, anti-angiogenesis and epigenetic modulation) through which they exert anti-carcinogenic effects to regulate multiple different molecular signaling pathways and biochemical processes mediated or induced by carcinogens. Based on maxi-multiple epidemiological and laboratory evidences, routine application or consumption of these natural agents may sufficiently shield the damaging effects of solar UVR and other cutaneous carcinogens in the environment. Ultimately, agents combined with cutaneous care cosmetics or sunscreens may provide a reasonable strategy for reducing the incidence rates of cutaneous carcinomas and other cutaneous diseases.

Still, the relationship between cutaneous carcinoma and intake of dietary phytochemicals remains largely unknown and should be further explored. Despite abundant laboratory and epidemiological evidences, more human randomized controlled trials (RCTs) are still needed to further assess the preventive effects of these phytochemicals on cutaneous carcinoma. Human beings have a big difference from experimental animals in pharmacokinetic characteristics. Thus, both pharmacokinetic properties and bioavailability are key issues in investigating the dietary prevention of cancer and should be assessed carefully before undertaking human RCTs.

In recent years it has become more and more obvious that experimental figures obtained in vivo are very often followed by unacceptable results in clinic. A hopeful strategy to overcome this problem includes the development of suitable carrier systems. The key advantage is that the in clinic fate of the drug is no longer merely determined by the characteristics of the drug, but by the carrier system, which must permit a localized and controlled drug release achieved through topical and systemic delivery systems. Thus, series of drug carrier system (such as nanocarriers nanoparticles, nanoemulsions, liposomes, micelles, vesicles, soluble polymer–drug conjugates, etc) need to be further exploit and utilize, which may improve the effect of diet phytochemicals on cutaneous carcinoma prevention in clinic.

In addition, while it is encouraging that single dietary phytochemicals have meglio chemopreventative properties in a range of different models in most experimental study, it is worth noting that the combined effects of multiple dietary chemopreventative compounds are scarcely reported. Cutaneous carcinoma development is a multistep process and diverse pathological conditions and signaling pathways are involved in. Thus, whether using a combination of phytochemicals can provide synergistic or additive preventive effects through the different pathway in the complicated process of cancerization need to be further demonstrated in both laboratory and clinical studies.

Moreover, cancer incidence risk, prognosis and response to treatment differ among individuals, so they can be effectively treated only by utilizing individualized regimens. Till now, a personalized diet for preventing cancers, although feasible in theory, has not been well documented. Thus, to control cutaneous carcinoma through chemoprevention, we need to identify the right patient population and the right agents simultaneously. In the future, we will endeavor to find out risk factors of cutaneous carcinoma, gene signatures and corresponding pathological reaction relationships to identify the high-risk population, to propose targeted preventive therapies with diverse dietary phytochemicals, and to finally benefit each individual. To summarize, to make chemoprevention a successful strategy for cutaneous carcinoma in use of dietary phytochemicals, aimed at identifying the right patient population, the right agents and the right drug carrier systems need to be investigated simultaneously.

Abbreviations:

Akt

protein kinase B

AMPK

adenosine 5′-monophosphate (AMP)-activated protein kinase

Ang

angiopoietin

AP-1

activator protein 1

ARE

antioxidant-responsive element

ATF-2

activating transcription factor 2

BCC

basal cell carcinoma

Bcl-2

B-cell lymphoma 2

Bcl-Xl

B-cell lymphoma-extra large

Bmi-1

B lymphoma Mo-MLV insertion region 1 homolog

CCL2

chemokine (C-C motif) ligand 2

CDK

cyclin-dependent kinases

c-FLIP

cellular Fas-associated death domain-like interleulin-1 β converting enzyme inhibitory protein

CF-TP

polyphenol fraction of Crataegus pinnatifida

COX-2

cyclooxygenase-2

CPDs

cyclobutane pyrimidine dimers

CREB

cAMP response element-binding protein

CXCL8

chemokine (C-X-C motif) ligand 8

DATS

diallyl trisulfide

DMBA

7,12-dimethylbenz[a]anthracene

DNMTs

DNA methyltransferases

EC

endothelial cells

ECM

extracellular matrix

EGCG

epigallocatechin gallate

EP

prostaglandin E2 receptor

ERK

extracellular signal–regulated kinases

Ezh2

enhancer of zeste homolog 2

FAK

focal adhesion kinase

FGF

fibroblast growth factors

GCL

glutamate cysteine ligase

GM-CSF

granulocyte-macrophage colony-stimulating factor

GPx

glutathione peroxidase

GSH

glutathione

GST

glutathione S-transferases

HATs

histone acetyltransferase

HDACs

histone deacetylase

HDMs

histone demethylase

HH

hedgehog

HIF-1α

hypoxia-inducible factor-1 alpha

HMTs

histone methyltransferases

HO-1

heme oxygenase 1

HPVs

human papilloma viruses

IBD

inflammatory bowel disease

IKK

IκB kinase

IL

interleukin

iNOS

inducible nitric oxide synthases

JNK

c-Jun N-terminal kinases

Keap1

kelch-like-ECH-associated protein 1

LPSs

lipopolysaccharides

MAPK

mitogen-activated protein kinases

MC1R

melanocortin 1 receptor

MDA

malonaldehyde

MITF

microphthalmia-associated transcription factor

MMP

matrix metalloproteinase

m-TOR

mammalian target of rapamycin

TXA2

thromboxane A2

MVD

microvascular density

NF-κB

nuclear factor kappa-light-chain enhancer of activated B cells

NMSC

non-melanocytic cutaneous carcinoma

NO

nitric oxide

NQO

NAD(P)H:quinoneoxidoreductase

Nrf2

nuclear factor (erythroid-derived 2)-like 2

PCNA

proliferating cell nuclear antigen

PDGF

platelet-derived growth factor

PGE2

prostaglandin E2

PGI2

prostaglandin I2

PI3K

phosphatidylinositol-3-kinases

PKC

protein kinase C

PLGF

Placental growth factor

PTEN

phosphatase and tensin homolog

ROS

reactive oxygen species

SCC

squamous cell carcinoma

STAT3

signal transducer and activator of transcription 3

TIMP-1

tissue inhibitor of metalloproteinases 1

TLR4

toll-like receptor 4

TNF-α

tumor necrosis factor alpha

TPA

12-O-Tetradecanoylphorbol-13-acetate

TSP-1

thrombospondin 1

UVR

ultraviolet radiation

VEGF

vascular endothelial growth factor

XIAP

X-linked inhibitor of apoptosis protein

γ-GCS

γ-glucocorticoids

TSG

tumor suppressor genes