Targeting Melanoma via Drug Repurposing: Investigating Melatonin Synergy and Melanin-Driven Resistance in 2D Cell Line Models ^†

Melanoma is a highly aggressive form of skin cancer known for its swift acquisition of resistance to treatment, particularly therapies targeting the Mitogen-Activated Protein Kinase (MAPK) signaling cascade [1]. Repurposing existing drugs presents a strategic and cost-effective method for discovering complementary treatments that may improve clinical outcomes. Among these candidates, melatonin, a multifunctional molecule with recognized anticancer properties, has attracted interest for its ability to influence melanoma cell behavior and improve responsiveness to conventional therapies. Studies using 2D cultures of melanoma cell lines, including those with both B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) mutations and wild-type profiles, suggest that melatonin exerts anti-proliferative and apoptosis-inducing effects. Its combination with BRAF and MEK (mitogen-activated extracellular signal regulation kinase) inhibitors appears to enhance the cytotoxic effect and diminish resistance [2]. Simultaneously, pigmentation within melanoma cells has been identified as a variable influencing therapeutic outcomes. Experimental findings suggest that melanin can bind and retain chemotherapeutic agents, lowering intracellular drug availability and reducing oxidative stress, thereby diminishing drug efficacy in pigmented melanoma cells. Mechanistically, melatonin is proposed to exert its influence by downregulating MAPK and PI3K (Phosphatidylinositol 3-kinase) pathways and promoting mitochondrial caspase activation. Additionally, melanin-rich cells tend to generate fewer reactive oxygen species under treatment conditions, further supporting the notion of melanin functioning as a biochemical shield against therapy.

These in vitro observations are consistent with results from in vivo models, where melatonin has been shown to potentiate the antitumor effects of BRAF-targeted agents in melanoma. In murine xenograft studies, co-treatment with melatonin and vemurafenib led to greater tumor suppression than either agent alone, potentially through inhibition of the NF-κB/iNOS/hTERT pathway and a reduction in stem-like tumor characteristics [3]. Analogs of melatonin have similarly demonstrated efficacy in reducing tumor growth and downregulating MAPK pathway activity in animal models [4]. Taken together, these findings advocate for melatonin as a viable adjuvant therapy and underscore the importance of accounting for tumor pigmentation in drug development and evaluation.