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Review
. 2025 May 13;12(1):2505400.
doi: 10.1080/20450885.2025.2505400. Epub 2025 May 16.

Updates in clinical trial-explored chemopreventive agents for cutaneous melanoma: mechanisms affecting melanocytes

Gelare Ghajar-Rahimi  1 , Nabiha Yusuf  1   2
Affiliations
Review

Updates in clinical trial-explored chemopreventive agents for cutaneous melanoma: mechanisms affecting melanocytes

Gelare Ghajar-Rahimi et al. Melanoma Manag. .

Abstract

Cutaneous melanoma is a highly aggressive skin cancer with rising incidence, driven by risk factors such as ultraviolet exposure, genetic predisposition, and immunosuppression. While surgical excision remains the primary treatment, interest in chemoprevention strategies is growing. Numerous natural and synthetic agents have shown preclinical promise, but evaluating their effectiveness is challenging due to their systemic effects on multiple cell types. This review provides a focused examination of the melanocyte-specific mechanisms of select agents that have been tested in clinical trials for melanoma chemoprevention. We discuss various molecular and cellular mechanisms driving the anti-melanoma properties of nonsteroidal anti-inflammatory drugs, statins, sulforaphane, vitamin D, and N-acetylcysteine. Despite promising preclinical and early clinical data, challenges remain regarding precise mechanisms, optimal dosing, long-term safety, and patient selection. Future research should focus on refining melanoma prevention strategies through well-designed clinical trials and personalized approaches integrating genetic and molecular risk factors.

Keywords: Chemoprevention; N-acetylcysteine; aspirin; cutaneous; melanoma; statin; sulforaphane; vitamin D.

Plain language summary

There is a dearth of clinical trials studying chemoprevention of melanoma, particularly compared to the number examining non-melanoma skin cancers.To date, only NSAIDs, sulforaphane, lovastatin, atorvastatin, vitamin D, and N-acetylcysteine have been studied in human clinical trials specifically designed to evaluate melanoma prevention. These agents influence melanoma cells through various mechanisms:NSAIDs inhibit COX-2 and NF-κB pathways, inducing cytotoxic effects through mitochondrial dysfunction, ROS generation, and immune system modulation.Sulforaphane activates antioxidant and apoptotic pathways, modulating immune responses, and impairing melanoma cell migration.Statins inhibit melanoma cell proliferation and induce apoptosis by disrupting IGF-1 receptor glycosylation, modulating RhoC activity, and downregulating NF-κB.Vitamin D, through its active form calcitriol, regulates melanoma cell viability and apoptosis by modulating key pathways like ERK and PTEN, with its effects varying based on VDR expression and cell line characteristics.N-acetylcysteine has antioxidant effects that can protect against UV-induced DNA damage and melanoma onset in some preclinical models.Continued research into both systemic effects and molecular mechanisms is essential to overcoming challenges and optimizing melanoma chemoprevention strategies.

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Conflict of interest statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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