Natural Products for Treatment of Skin Cancer

Abstract

Skin cancer is the most common cancer worldwide, with high mortality rates. Natural products have been useful for treating and developing several anticancer drugs over the years since their chemopreventive, anti-inflammatory, anti-oxidant, and anticancer activity. Therefore, this review examines and summarizes different plant-based and naturally derived agents with their respective mechanisms of action that have been used or tested to treat skin cancer to provide potential candidates for their use in the pharmacological formulation. Based on the collected information, it was concluded that natural products exhibit potential anticancer activity using signaling pathways that can supply limitations over conventional treatments as bioavailability and drug resistivity. However, more clinical trials and studies should be performed to develop new anti-skin cancer drugs from these natural product sources.

Background and Scope

Skin cancer is the most common form of cancer around the world. It is produced when damaged DNA prompts mutations that lead to uncontrolled growth and multiplication of epidermis cells, forming malignant tumors. There are two principal types of skin cancer; melanoma and non-melanoma skin cancer (NMSCs). Melanoma skin cancer is developing from the cells that produce the melanin known as melanocytes, and it is responsible for the major mortalities related to cancer. Non-melanoma skin cancer mainly affects the Caucasian population and includes basal cell carcinoma, squamous cell carcinoma, and Bowen’s disease.

Ultraviolet radiation is recognized as one of the main causes of skin cancer development since it is responsible for DNA damage and genetic muta- tions in the skin. Nevertheless, early diagnostic and adequate skin cancer treatment in their first stages leads to a high probability of curing or eliminating it. Several treatments are used to treat skin cancer, like radiation therapy, photodynamic therapy, topical chemotherapy, surgery, etc. The use of each of them depends on the type and stage of skin cancer presented by the patient. In this context, plants and natural products have positioned themselves as the best option for consumers for their healthy approach and its important role in traditional medicine due to availability,lower risk of side effects, affordability, and high efficacy against diseases.

Therefore, this work’s scope is examining and evaluating different plant-based and naturally occurring agents, including their underlying mechanism, that have been used or tested to treat skin cancer to provide potential candidates for their use in the pharmacological formulation. For this purpose, it has been revised scientific literature found in electronic databases including Scifinder, ScienceDirect, Skin Cancer Foundation website, NHI (National Library of Medicine), and GoogleScholar. The selection criteria consist of literature published from 2010 to 2021, English language, and related topics like cancer, skin cancer, melanoma, cell carcinoma, natural products, or plant. Under these criteria, only 15 articles were selected and summarized for this study.

Natural Agents for Skin Cancer Treatment

1 Polyphenols

In the last decades, polyphenols have been called attention as anticancer potential candidates because of their ability to control malignant cell metastasis. Polyphenols are natural antioxidants that comprise a great variety of secondary metabolites present in the human diet. Their anticancer and preventive activity against skin cancer metastasis is attributed not only to their antioxidant property but also their pro-oxidant effect, which makes them able to cause apoptosis in cancer cells through ROS genration.

On one hand, these compounds’ advantages include their biological activity’s stability under body conditions and their ability to be easily absorbed in the gut interfaces. On the other hand, the low bioavailability and absorption are some disadvantages of polyphenols as pharmacological agents; Polyphenols need to suffer biotransformation via several enzymes located in the intestine and colon for effective absorption, and their bioavail- ability is affected by gut microbiota.

Therefore, to solve these problems, approaches like nano- derivation, co-administration, and bioengineering strategies were developed. A variety of polyphenols are anticancer agents that act through different signaling pathways in exclusive targeting systems. Some examples of these polyphenols are discussed below:

Resveratrol

Resveratrol is a stilbenoid and phytoalexin mainly found in grapes, which exhibits antioxidant activity and anticancer effects on the skin, breast, and other cancer types. Regarding its bioavailability, up to 70% of the orally consumed resveratrol is absorbed in the body. Preclinical studies made in mouse skin carcinogenesis and animal mammary tumors have been proving that resveratrol’s antigrowth mechanism is based on anti-inflammatory and antioxidant effects, apoptosis induction, modulation of epigenetic and genetic factors, and cell cycle suppression. Here, the induction of the cell cycle suppression, which occurs at the S phase, is achieved by phosphorylation of Cdc2-tyr15 via ATM/ATR-Chk1/2- Cdc25C pathway. The D1, D2, and E cyclin’s reduced expression, triggered by resveratrol, suppresses the epidermal carcinoma cells’ proliferation in humans.

Quercetin

Quercetin is the most abundant flavonoid commonly found in the human diet, like apples, berries, red onions, and red grapes in high concentrations. Many studies performed in vivo and in vitro suggest that quercetin avoids cell growth, proliferation, and cycle progression of melanoma cells. STAT3 is a transcription protein responsible for cell survival and proliferation, and it plays an important role in melanomagenesis or melanin synthesis. Quercetin prevents the activation of a STAT3 signaling pathway in human melanoma cells by IL-6 inhibition, which is responsible for STAT3 phosphorylation. Also, it decreases the expression of the gene cyclin D1 associated with the STAT3 and the excretion of MMP-2, which is an enzyme involved in cell migration and a pivotal indicator of cancer metastasis.

This natural agent is a potential candidate for the treatment of melanoma for two reasons; its bioavailability of up to 60% for oral ingestion and overriding one of the most common problems in traditional cancer treatments, the chemoresistance to drugs.

Curcumin

Curcumin is a polyphenol mainly produced by Curcuma longa plants that possess medical properties used over the years to treat several diseases. Some of these properties include antiviral, antioxidant, anti-inflammatory, anti-proliferative, and anticarcinogenic action. Despite the medical uses and application of curcumin are well known for years, the mechanism of action that produces these effects has been established in recent years. The proposed mechanism for the antimetastatic action of Curcumin is based on apoptosis induction and cell viability suppression. Scientific evidence suggests that curcumin inhibits the activation and phosphorylation of STAT3 by IL-6 pleiotropic cytokine and inhibits the NF-jB transcription factor, reducing inflammation in the skin.

Epigallocatechin-3-gallate (EGCG)

It is a soluble flavan-3-ol compound found mainly in green tea. Some studies relate the low probability of prostate cancer with green tea consumption in Eastern countries. The anticancer and preventive activity of the EGCG is based on its anti-proliferative effect and its ability to induce apoptosis and suppress the cell cycle in melanoma cells. The mechanism of action of EGCG involves different pathways; for example, the retinoblastoma (pRb)-E2F/DP pathway that is responsible for the EGCG anti-proliferative effect, and downregulation and phosphorylation of the pRb, which leads to the suppression of the cell cycle progression in the G0/G1 phase and cell apoptosis. EGCG also inhibits the phosphorylation of STAT3, promotes the repairmen of DNA, and control the expression of genes associated with tumors.

Apigenin

Many experimental studies have proven the anticancer and preventive action of Apigenin; a naturally derived flavonoid commonly found in apples, grapefruit, onions, and chamomile. The health-promoting properties of Apigenin include anti-inflammatory, antioxidant, antiproliferative, and antiangiogenic activity against different types of cancer, especially skin cancer. Its anticancer action lies in modulating key targets and signaling pathways responsible for cell cycle, apoptosis, metastasis, and angiogenesis in melanoma cells; it suppresses the mTOR, and STAT3 activity through IL-6 inhibition.

2 Terpenoids

Terpenoids are secondary metabolites derived from five-carbon building units known as isoprene. This is the largest class of natural products comprising about 60% of the natural products identified. Depending on the number of carbons in their structure, there are different subclasses of terpenoids such as monoterpenoids, sesquiterpenoids, diterpenoids, triterpenoids, tetraterpenoids, and polyterpenoids.

These wide varieties make terpenoids potential candidates in the field of drug discovery. Some plant extracts, which mainly contain terpenoids, have been shown cytotoxic activity against melanoma cells in vitro and in vivo through apoptosis induction, oxidative stress, and cell proliferation suppression. Some of these class compounds are analyzed below:

Limonene

It is a monocyclic monoterpene that is mainly found in the essential oils of citric fruits. Limonene naturally occurs in two enantiomeric configurations or optical isomers: L and D, where D is the most common and studied in anti-cancer research. D-limonene has proven to be effective in treating and chemoprevention of different types of cancer, including skin cancer, during studies made in animal models. Due to anti-oxidant, antiangiogenic, and proapoptotic effects, D-limonene inhibits metastasis and tumor growth. It is unclear the D-limonene mechanism of action, but it is believed that it inhibits the small G proteins isoprenylation through suppressing the HMG-CoA reductase.

Oridonin

Oridonin is a diterpenoid mainly isolated from Rabdosia rubescens, which is a Chinese herb with medical applications. This compound has been demonstrated activity against skin carcinoma and uveal melanoma besides other types of cancer as osteoma in recent years. Scientific evidence has shown that oridonin induces cell death or apoptosis in melanoma cells through suppression of NFkB signaling pathway thought the inhibition of its binding to DNA. An investigation holds that oridonin and nodistodin (another diterpenoid) can suppress melanin’s cellular production known as melanogenesis and exhibits cytotoxicity against murine B16-F10 melanoma. These studies prove that Oridonin is a potential candidate to treat skin cancer.

Beta-Carotene

Beta-Carotene is a tetraterpenoid that belongs to the carotenoids class. It is one of the most studied carotenoids since it is the most abun- dant in the human diet. Some sources of this compound include carrots, pumpkin, spinach, and pepper. Beta-Carotene can cause apoptosis in murine melanoma cells through the regulation of p53, Bcl-2, and caspase-3 cancer genes. It is known that p53 is responsible for the cell cycle checkpoint activation and Bcl-2 inhibits cell death. Also, it was proved that a diet with a high content of carotenoids, including beta-carotene, is associ- ated with a low risk to suffer melanoma.

Fucoxanthin

Fucoxanthin is a xanthophyll found in the brown algae chloroplasts. This natural compound can reduce the potential of metastasis in murine melanoma cells and, as well as beta-carotene, it can induce apoptosis, regulating the caspase signaling pathway. Other fucoxanthin actions comprise the cell cycle arrest, anti-proliferation, and tumor reduction activity.

3 Sulfur-containing phytochemicals

The biosynthesis of secondary metabolites in living systems involves the participation of many essential compounds like Sulphur. The sulfur-containing phytochemicals are compounds that contain Sulphur in their chemical structure, and some examples include alliins, sulforaphane, phytoalexins, allyl sulfides, and thionins. These metabolites family have been proved to have a broad spectrum of health-promoting benefits such as anti-inflammatory, antitumor, chemopreventive, and antioxidant properties. There is scientific evidence that supports that some of these sulfur-containing phytochemicals exhibits activity against skin cancer, and they are revised below:

Allyl sulfides

Allyl sulfides are metabolites mainly found in garlic oil and are responsible for its health benefits, including tumor anti-inflammatory, antioxidant, and antiproliferation action. Garlic is a plant that belongs to the Allium genus that has been widely used in alternative medicine. Its consumption has been associated with a reduced risk of suffering several types of cancer like lung, gastric, skin, and prostate. Diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS) are allyl sulfide compounds derived from the allicin decomposition produced by the crushing process of the garlic cloves. A study holds that diallyl trisulfide (DATS) has the most potent activity against skin cancer since it inhibits the growth of melanoma cells and basal cell carcinoma in humans. Several mechanisms for the allyl sulfides anticancer action have been proposed, and two of them consist in the damage of DNA and an increment of ROS by inducing apoptosis, endoplasmic reticulum stress, and G2/M arrest.

This last, G2/M, is a cell cycle checkpoint responsible for cell mitosis. Therefore, an advantage of allyl sulfides in skin cancer treatment is their ability to act by multiple signaling pathways targeting.

Sulforaphane

Sulforaphane is a natural isothiocyanate present in cruciferous vegetables like broccoli, cabbage, radish, and Brussel sprouts. Its pharmacological benefits, where its potential activity stands out, have made sulforaphane the focus of many biological studies and clinical trials. Also, the inhibition of skin carcinogenesis by UV exposition has been associated with high sulforaphane consumption in the diet. These compounds’ anticancer activity comprises cell proliferation inhibition, apoptosis induction, and suppression of metastasis.

Sulforaphane induces apoptosis by protein kinase and factor-kappa B inactivation in tumor cells and overproduction of reactive oxygen species (ROS). Alyoussef et al. investigated the sulphone antitumor activity in skin cancer mice model and found that this phytochemical inhibits the sulfatase-2 enzyme activity, associated with tumor progression,with successive HSPGs pro- motion and glypican-3 reduction.

4 Alkaloids

Alkaloids are a diverse group of secondary metabolites that contain nitrogen in their structure. They are widely distributed in the plant kingdom and are usually found in the plants’ leaves, bark, and roots. Plants use the alkaloid’s toxicity as a defense mechanism against predators or pathogens. Thus, high doses of this metabolite can be poisonous, but they are useful as pharmaceutical agents in lower doses. The therapeutic properties of these important biologically active compounds include their analgesic action and anticancer effect. In vitro and in vivo studies have been proven that alkaloids possess antiproliferative and anti-metastasis activity in different types of cancer, including skin cancer.

Some of the alkaloids with potential properties for the treatment of skin cancer are discussed below:

Berbine

Berbine is an isoquinoline alkaloid mainly found in the roots, stems, and bark of Berberis genus plants like barberry (Berberis vulgaris) and tree turmeric (Berberis aristata). This alkaloid is used in traditional Chinese medicine since it exhibits anti-carcinogenic, anti-diabetic, antiinflammatory, and antibacterial activity. Regarding its anticancer activity, anti-proliferative, apoptosis induction, inhibition of cell viability, pro-oxidative, and anti-metastasis are some of the therapeutic anticancer effects of Berbine. The mechanism of action of the Berbine has been related to the inhibition of COX-2, PGE reduction, and expression of EP2/ EP4 receptors. The suppression of the melanoma cell migration is produced by the inhibition of TPA and PGE2 and NF-kB levels reduction, and the anti-migratory effect is due to the cell apoptosis induction.

Harmine

Harmine is a beta-Carboline alkaloid obtained from the Paganum harmala plant. It is widely used in alternative medicine due to its antibacterial, neuropharmacological, and anti-tumor effects. In vivo and in vitro studies have been proven that Harmine has anti-metastasis and anti-angiogenic properties; this phytochemical suppressed the formation of tumor nodules in the lung tissues of mice with melanoma. The proposed mechanism for the anti-angiogenic action of the Harmine consists in the suppression of transcription factors associated with the tumor growth, such as CREB, ATF-2, and (NF)-kB factor.

Alpha-Solanine

Alpha-Solanine is a soluble glycoalkaloid mainly obtained from leaves, stems, and shoots of Solanaceae especies. This is a toxic alkaloid since the plants use it as a defense mechanism against predators. However, studies have been shown that a low, non-toxic level of alpha-Solanine induces apoptosis, suppresses proliferation, and blocks the growth of human carcinoma cells. Its anti-tumor activity is related with the E-cadherin overexpression, (MMP)-2 and (MMP)-9 matrix metalloproteinase reduction, and inhibition of NF-kB activity.

Conclusions and Outlook

This review summarized the different chemotherapeutic and chemopreventive properties of different naturally derived products that have been shown to have potential activity against skin cancer. The different foods in the human diet where these metabolites are commonly found were identified, thus associating their consumption with the low risk of suffering from certain types of cancer, including skin cancer.

Likewise, the different mechanisms of action for each of the metabolites discussed were described based on different reviewed biological studies. In this way, it was possible to notice that these phytochemicals’ anticancer properties are related to the control of inflammation, metastasis, proliferation, apoptosis, oxidation, and suppression of the cell cycle in cancer cells where the main mechanisms of action are via STAT3, (pRb) -E2F / DP, GGpp / Rho, NF-kB, and COX-2 / PGE 2 pathways.

Finally, it was confirmed that most of the natural products discussed before can inhibit more than one signaling pathway against skin cancer proliferation and survival. These multiple mechanisms of action, low risk of side effects, inexpensively, and bioavailability makes them suitable candidates for the treatment and prevention of skin cancer than the conventional treatments. However, more trials and clinical studies need to be done to properly use the natural products discussed above in the treatment of skin cancer or even produce new pharmaceuticals or therapy methods.

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