Table of ContentsSummaryBackground and ScopeNatural Agents for the Treatment of Skin Cancer1 Polyphenols2 Terpenoids3 Sulfur-Containing Phytochemicals4 AlkaloidsConclusions and PerspectivesReferencesSummarySkin cancer is the most common cancer in the world, with high mortality rates. Natural products have been useful in treating and developing several anticancer drugs over the years due to their chemopreventive, anti-inflammatory, antioxidant, and anticancer activity. Therefore, this review examines and summarizes different herbal 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 treatment of skin cancer. pharmacological formulation. Based on the information collected, it was concluded that natural products exhibit potential anticancer activity using signaling pathways that may have limitations compared to conventional treatments, such as drug bioavailability and resistivity. However, more trials and clinical studies should be carried out to develop new skin cancer drugs from these natural product sources. Say no to plagiarism. Get a tailor-made essay on “Why Violent Video Games Should Not Be Banned”? Get the original essayBackground and ScopeSkin cancer is the most common form of cancer worldwide. It is produced when damaged DNA causes mutations that lead to uncontrolled growth and multiplication of cells in the epidermis, thereby forming malignant tumors. There are two main types of skin cancer; melanoma and non-melanoma skin cancer (NMSC). Melanoma skin cancer develops from cells that produce melanin called melanocytes and is responsible for the main cancer-related deaths. Non-melanoma skin cancer primarily affects the Caucasian population and includes basal cell carcinoma, squamous cell carcinoma, and Bowen disease. Ultraviolet radiation is recognized as one of the main causes of the development of skin cancer because it is responsible for DNA damage and genetic mutations. in the skin. Nevertheless, early diagnosis and adequate treatment of skin cancer in its early stages leads to a high probability of curing or eliminating it. Several treatments are used to treat skin cancer, such as radiotherapy, 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 are positioned as the best option for consumers due to their healthy approach and their important role in traditional medicine due to their availability, low risk of side effects, their affordable price and their high effectiveness against diseases. The objective is to review and evaluate different plant-derived and natural 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. To this end, scientific literature found in electronic databases including Scifinder, ScienceDirect, the Skin Cancer Foundation website, NHI (National Library of Medicine), and GoogleScholar was reviewed. The selection criteria relate to literature published from 2010 to 2021, in English and on related topics such as cancer, cancer of theskin, melanoma, cellular carcinoma, natural products or plants. According to these criteria, only 15 articles were selected and summarized for this study. Natural Agents for Skin Cancer Treatment1 Polyphenols In recent decades, polyphenols have attracted attention as potential anticancer candidates due to their ability to control metastasis of malignant cells. Polyphenols are natural antioxidants that include a wide variety of secondary metabolites found in the human diet. Their anticancer and preventive activity against skin cancer metastases is attributed not only to their antioxidant property but also to their pro-oxidant effect, which makes them capable of causing apoptosis of cancer cells via the generation of ROS. On the one hand, the advantages of these compounds include the stability of their biological activity under body conditions and their ability to be easily absorbed in intestinal interfaces. On the other hand, low bioavailability and absorption constitute some disadvantages of polyphenols as pharmacological agents; Polyphenols must undergo biotransformation via several enzymes located in the intestine and colon for efficient absorption, and their bioavailability is affected by the gut microbiota. Therefore, to solve these problems, approaches such as nanoderivatization, co-delivery and bioengineering strategies have been developed. A variety of polyphenols are anticancer agents that act through different signaling pathways in proprietary targeting systems. Some examples of these polyphenols are shown below: ResveratrolResveratrol is a stilbenoid and phytoalexin found primarily in grapes, which exhibits antioxidant activity and anticancer effects on the skin, breast and other types of cancer. Regarding its bioavailability, up to 70% of resveratrol consumed orally is absorbed into the body. Preclinical studies performed on mouse skin carcinogenesis and animal mammary tumors have proven that the anti-growth mechanism of resveratrol relies on anti-inflammatory and antioxidant effects, induction of apoptosis, modulation of epigenetic and genetic factors. and cell cycle suppression. Here, induction of cell cycle suppression, which occurs at S phase, is achieved by phosphorylation of Cdc2-tyr15 via the ATM/ATR-Chk1/2-Cdc25C pathway. Reduced expression of cyclins D1, D2 and E, triggered by resveratrol, suppresses the proliferation of epidermal carcinoma cells in humans. QuercetinQuercetin is the most abundant flavonoid commonly found in the human diet, such as apples, berries, red onions, and red grapes. high concentrations. Numerous in vivo and in vitro studies suggest that quercetin prevents cell growth, proliferation and cycle progression of melanoma cells. STAT3 is a transcription protein responsible for cell survival and proliferation and plays an important role in melanogenesis or melanin synthesis. Quercetin prevents activation of a STAT3 signaling pathway in human melanoma cells through inhibition of IL-6, which is responsible for STAT3 phosphorylation. Furthermore, it decreases the expression of the STAT3-associated cyclin D1 gene and the excretion of MMP-2, which is an enzyme involved in cell migration and a critical indicator of cancer metastasis. This natural agent is a potential candidate for the treatment of melanoma for two reasons; its bioavailability can reach 60% for oral ingestion and overcomes one of the most common problems in treatmentstraditional methods against cancer and chemoresistance to drugs. Curcumin Curcumin is a polyphenol mainly produced by the Curcuma longa plants which have medical properties used over the years to treat several diseases. . Some of these properties include antiviral, antioxidant, anti-inflammatory, antiproliferative and anticarcinogenic action. Although the medical uses and applications of curcumin have been 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 the induction of apoptosis and suppression of cell viability. Scientific evidence suggests that curcumin inhibits the activation and phosphorylation of STAT3 by the pleiotropic cytokine IL-6 and inhibits the transcription factor NF-jB, thereby reducing skin inflammation.Epigallocatechin-3-gallate (EGCG) It is a soluble flavan-3-ol compound found primarily in green tea. Some studies associate the low probability of prostate cancer with the consumption of green tea in Eastern countries. The anticancer and preventive activity of EGCG is based on its antiproliferative effect and its ability to induce apoptosis and suppress the cell cycle of melanoma cells. The mechanism of action of EGCG involves different pathways; for example, the retinoblastoma (pRb)-E2F/DP pathway which is responsible for the antiproliferative effect of EGCG, as well as the downregulation and phosphorylation of pRb, which leads to the suppression of progression of cell cycle in the G0/G1 phase and in cells. apoptosis. EGCG also inhibits STAT3 phosphorylation, promotes DNA repair, and controls the expression of tumor-associated genes.ApigeninNumerous experimental studies have proven the anticancer and preventive action of apigenin; a naturally occurring 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 the modulation of key targets and signaling pathways responsible for cell cycle, apoptosis, metastasis and angiogenesis in melanoma cells; it suppresses mTOR and STAT3 activity through inhibition of IL-6.2 TerpenoidsTerpenoids are secondary metabolites derived from five-carbon building blocks known as isoprene. It is the largest class of natural products comprising approximately 60% of identified natural products. 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 large varieties make terpenoids potential candidates in the field of drug discovery. Some plant extracts, which mainly contain terpenoids, have shown cytotoxic activity against melanoma cells in vitro and in vivo through induction of apoptosis, oxidative stress and suppression of cell proliferation. Some of these class compounds are analyzed below: Limonene This is a monocyclic monoterpene found primarily in citrus essential oils. Limonene occurs naturally in two enantiomeric or optical isomeric configurations: L and D, where D is the most common and studied in anticancer research. D-limonene has been shown to be effective in the treatment and chemoprevention of different types of cancer, including cancerof the skin, during studies carried out on animal models. Due to its antioxidant, antiangiogenic and pro-apoptotic effects, D-limonene inhibits metastasis and tumor growth. The mechanism of action of D-limonene is unclear, but it is thought to inhibit isoprenylation of small G proteins by suppressing HMG-CoA reductase. Oridonin Oridonin is a diterpenoid mainly isolated from Rabdosia rubescens, a Chinese herb with medical applications. This compound has demonstrated activity against skin carcinoma and uveal melanoma in addition to other types of cancer such as osteoma in recent years. Scientific evidence has shown that oridonin induces cell death or apoptosis of melanoma cells through suppression of NFkB signaling pathway and inhibition of its DNA binding. Investigation reveals that oridonin and nodistodine (another diterpenoid) can suppress cellular production of melanin called melanogenesis and exhibit cytotoxicity against murine melanoma B16-F10. These studies show that Oridonin is a potential candidate for treating skin cancer. Beta-caroteneBeta-carotene is a tetraterpenoid that belongs to the carotenoid class. It is one of the most studied carotenoids since it is the most abundant in the human diet. Some sources of this compound include carrots, pumpkin, spinach and pepper. Beta-carotene can cause apoptosis of murine melanoma cells through the regulation of cancer genes p53, Bcl-2 and caspase-3. It is known that p53 is responsible for activation of the cell cycle checkpoint and that Bcl-2 inhibits cell death. A diet rich in carotenoids, including beta-carotene, has also been shown to be associated with a low risk of melanoma. FucoxanthinFucoxanthin is a xanthophyll present in the chloroplasts of brown algae. This natural compound may reduce the risk of metastasis in murine melanoma cells and, along with beta-carotene, it may induce apoptosis, regulating the caspase signaling pathway. Other actions of fucoxanthin include cell cycle arrest, anti-proliferation, and tumor-reducing activity.3 Sulfur-containing phytochemicalsThe biosynthesis of secondary metabolites in living systems involves the participation of many essential compounds like sulfur. Sulfur-containing phytochemicals are compounds that contain sulfur in their chemical structure, and some examples include alliins, sulforaphane, phytoalexins, allyl sulfides, and thionins. This family of metabolites has been proven to provide a broad spectrum of health benefits, such as anti-inflammatory, anti-tumor, chemopreventive, and antioxidant properties. There is scientific evidence that supports that some of these sulfur-containing phytochemicals exhibit activity against skin cancer, and it is reviewed below: Allyl sulfidesAllyl sulfides are metabolites found mainly in garlic oil and are responsible for its health benefits, including tumor anti-inflammatory, antioxidant and antiproliferation action. Garlic is a plant belonging to the genus Allium and widely used in alternative medicine. Its consumption has been associated with a reduction in the risk of suffering from several types of cancer such as lung, stomach, skin and prostate cancer. Diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS) are allyl sulfide compounds derived from the breakdown of allicin produced by the crushing process of garlic cloves . Study finds diallyl trisulfide (DATS) has the most potent activityagainst skin cancer, as it inhibits the growth of melanoma and basal cell carcinoma cells in humans. Several mechanisms for the anticancer action of allyl sulfides have been proposed, and two of them consist of DNA damage and increase of ROS by inducing apoptosis, endoplasmic reticulum stress and stop of the G2/M. The latter, G2/M, is a cell cycle checkpoint responsible for cell mitosis. Therefore, an advantage of allyl sulfides in the treatment of skin cancer is their ability to act through multiple targeting signaling pathways. SulforaphaneSulforaphane is a natural isothiocyanate found in cruciferous vegetables such as broccoli, cabbage, radish and Brussels sprouts. Its pharmacological benefits, where its potential activity stands out, have made sulforaphane the subject of numerous biological studies and clinical trials. Furthermore, inhibition of skin carcinogenesis by UV exposure has been associated with high consumption of sulforaphane in the diet. The anticancer activity of these compounds includes inhibition of cell proliferation, induction of apoptosis and suppression of metastasis. Sulforaphane induces apoptosis through inactivation of protein kinase and factor kappa B in tumor cells and overproduction of reactive oxygen species (ROS). Alyoussef et al. studied the antitumor activity of sulfones in a skin cancer mouse model and found that this phytochemical inhibits sulfatase-2 enzyme activity, associated with tumor progression, with successive promotion of HSPGs and a reduction in glypican-3.4 AlkaloidsAlkaloids 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 leaves, bark and roots of plants. Plants use the toxicity of the alkaloid as a defense mechanism against predators or pathogens. Thus, high doses of this metabolite can be toxic, but they are useful as pharmaceutical agents at low doses. Therapeutic properties of these important biologically active compounds include their analgesic action and anticancer effect. In vitro and in vivo studies have 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: BerbineBerbine is an isoquinoline alkaloid. It is mainly found in roots, stems and barks of plants of the genus Berberis such as barberry (Berberis vulgaris) and tree turmeric (Berberis aristata). This alkaloid is used in traditional Chinese medicine because it exhibits anti-carcinogenic, anti-diabetic, anti-inflammatory and antibacterial activity. Regarding its anticancer, anti-proliferative, induction of apoptosis, inhibition of cell viability, pro-oxidant and anti-metastasis activities are some of the anticancer therapeutic effects of berbine. The mechanism of action of berbine has been linked to COX-2 inhibition, PGE reduction, and EP2/EP4 receptor expression. The suppression of melanoma cell migration is produced by the inhibition of the reduction of TPA, PGE2 and NF-kB levels, and the anti-migratory effect is due to the induction of cell apoptosis. HarmineHarmine is a beta-carboline alkaloid obtained from the Paganum harmala plant. . It is widely used in alternative medicine due to its antibacterial, neuropharmacological and antitumor effects. In vivo and in vitro studies have proven that., 2010, 33, 1685–1691.