Melanoma Chemoprevention: Current Status and Future Prospects

Abstract

The incidence of skin cancers, both nonmelanoma and melanoma, is increasing in the United States. The ultraviolet radiation, mainly from sun, is considered the major cause for these neoplasms. While nonmelanoma skin cancers are far more numerous, melanoma remains the most challenging. This is because melanoma can become extremely aggressive and its incidence is increasing worldwide due to lack of effective early detection, as well as disease recurrence, following both surgery and chemotherapy. Therefore, in addition to better treatment options, newer means are required to prevent melanomas from developing. Chemoprevention is a reasonable cost-effective approach to prevent carcinogenesis by inhibiting the processes of tumor initiation, promotion and progression. Melanoma is a progressive disease, which makes it very suitable for chemopreventive interventions, by targeting the processes and molecular pathways involved in the progression of melanoma. This review discusses the roles of various chemopreventive agents such as NSAIDs, statins, vitamins and dietary agents in melanoma and highlights current advancements and our perspective on future of melanoma chemoprevention. Although considerable preclinical data suggest that melanoma may be prevented or delayed by a numerous chemopreventive agents, we realize there are insufficient clinical studies evaluating their efficacy and long-term safety for human use.

Figure 1

Schematic representation of ultraviolet (UV) radiation transmission in human skin and a proposed mechanism of melanoma progression from melanocytes after UV exposure. Solar radiation, tanning beds, UV lamps and other artificial light bulbs are all sources of UV exposure to human skin. UVA and UVB rays are mainly responsible for mutagenic effects on melanocytes and promotion of melanoma (indicated by the dashed lines). The inset box indicates the path of melanoma progression following exposure of UV light. The key genes that have been identified as having driver mutations in melanoma are outlined in the grey box on the left, including BRAF and NRAS, as well as other newly identified genes. Hyperactivation of RAS-RAF-MEK-ERK and PI3K-AKT-mTOR pathway genes have been suggested to be responsible for melanoma progression (grey boxes on the right).

Figure 2

Schematic representation of processes involved in ultraviolet (UV) radiation-mediated development of skin cancer, and examples of chemopreventive agents reported to be useful at different stages of the carcinogenic process. Normally, when skin is exposed to UV radiation, it initiates tumor formation by DNA damage, mutagenesis and release of reactive oxygen species. After damage to the cells, the initiated cells with mutations inferring greater growth potential expand to become pre-neoplastic lesions. If these lesions are not found and removed, they may progress through transformation and become malignant skin cancers and require treatment, which is not always successful (as indicated by the dashed up arrow). Additionally, many melanomas reoccur after successful treatment (dashed down arrow). Chemopreventive agents can be applied topically that directly block the UV rays from reaching to the skin, or can be used to reverse or delay the process of multi-stage carcinogenesis at one or at all of the stages, depending on their efficacy. The ideal chemoprevention regimen would target all stages of cancer development and may include a combination of two or more agents in order to obtain the greatest preventive effects against UV-induced melanoma.