(B-71) Inhibition of Pheomelanin Synthesis as a Novel Approach for Melanoma Prevention

Introduction:: Upwards of 1 million Americans currently live with melanoma, the deadliest type of skin cancer. This number is expected to increase, as the American Cancer Society estimates nearly 100,000 new melanoma diagnoses by the end of 2023. The annual cost of treatment is projected to exceed $3 billion, poised to strain the country’s healthcare system. Melanoma develops from the abnormal growth of pigment-producing cells called melanocytes in the skin tissue. Melanocytes produce two types of the pigment polymer melanin: eumelanin and pheomelanin. Pheomelanin is considered carcinogenic and phototoxic due to its higher redox potential and ability to generate reactive oxygen species, which can lead to oxidative stress and cause DNA damage, while eumelanin is considered to have antioxidant and photoprotective properties. Previous methods of inhibiting pheomelanin synthesis have included reducing both tyrosinase and α-MSH activity, which reduces the production of eumelanin as well; thus, the goal of this project is to investigate the potential of reducing cysteine concentrations to modulate melanin synthesis pathways.

Materials and Methods:: Both eumelanin and pheomelanin are synthesized from 3,4-dihydroxyphenylalanine (L-DOPA), which is catalytically oxidized to dopaquinone by the enzyme tyrosinase. Dopaquinone undergoes intramolecular cyclization to form cyclodopa, oxidized to dopachrome. Dopachrome is a precursor for the 5,6-dihydroxyindole (DHI), or 5,6-dihydroxyindole-2-carboxylic acid (DHICA), the monomers of eumelanin. In the presence of cysteine, dopaquinone forms cysteinyldopa, which forms benzothiazine or benzothiazole intermediate units, the precursors of the monomers of pheomelanin. In order to differentiate between the synthesis of eumelanin and pheomelanin, UV-Vis spectrophotometry was utilized. Dopachrome, an intermediate of eumelanin, has an absorption peak at 475 nm, which indicates the reaction has entered the eumelanin synthesis pathway; the absence of this peak suggests the formation of cysteinyldopa. Thus, this is a method of determining relative quantities of eumelanin and pheomelanin being produced. This research is developing a novel treatment geared towards breaking down cysteine and cysteine homologues to inhibit pheomelanin formation, promoting eumelanin synthesis.

Results, Conclusions, and Discussions:: Work done on this project thus far has identified an effective treatment to inhibit cysteine and its homologues. This suggests that there is potential for cysteine reduction as a chemopreventive approach to prevent pheomelanin synthesis, potentially reducing the associated carcinogenic and phototoxic effects. Further studies aim to obtain a more robust characterization of the final structures and intermediates of pheomelanin and eumelanin, as well as validate the findings found in vitro through the use of cellular models. This project aims to understand the effect of reducing cysteine concentrations on modulating melanin synthesis pathways, ultimately identifying a new approach to preventing melanoma and minimizing its impact on public health and healthcare costs.

Acknowledgements (Optional): : DOD Melanoma Program (MRP) – W81XWH2211041
Case Comprehensive Cancer Center, CanSUR Program
Lerner Research Institute

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