Exploitation of Pigment Biosynthesis Pathway as a Selective Chemotherapeutic Approach for Malignant Melanoma.

Abstract

Human malignant melanoma represents a difficult therapeutic challenge to both medical scientists and practicing physicians. However, the biologic uniqueness of the tumor may provide opportunities for exploitation in therapeutics. This study proposed to undertake a systemic approach to the chemotherapy of malignant melanoma based upon the uniqueness of pigment-cell metabolic pathway pertaining to conversion of tyrosine and dopa with subsequent formation of melanin by tyrosinase and its related enzymes. The sulphur homologue of tyrosine, cysteinylphenol (CP), its amine derivative, cysteaminylphenol (CAP), and their N-acetyl and alpha-methyl derivatives have been synthesized and tested in in vivo and in vitro melanocytotoxicity and antimelanoma effects. These phenolic thioethers (PTEs) and phenolic thioether amine (amides) (PTEAs), which are substrates of tyrosinase, showed significant cytotoxicity that is selective to melanocytes and melanoma cells. Most previous attempts to impair the melanin pathway as a therapeutic strategy have been of limited success because they have been directed to catecholic compounds that are unstable and insufficient in lethality at physiologically tolerable doses. By contrast, our approach relies on phenolic compounds, PTEs and PTEAs, which are more stable than catechols and become toxic only after oxidation by tyrosinase. We found PTEA as the most promising agent for the future development of chemotherapeutic agents. The possible biologic, chemical, and pharmacologic reactions of these synthetic compounds within the melanoma cells are studied and discussed.

Phenolic composition, in vitro antioxidant effects and tyrosinase inhibitory activity of three Algerian Mentha species: M. spicata (L.), M. pulegium (L.) and M. rotundifolia (L.) Huds (Lamiaceae)

“…Therefore, tyrosinase inhibitors may be clinically useful for the treatment of skin cancer (Jimbow et al, 1993). Also, recently, more attention is being paid to the use of natural plant extracts in the cosmetic industry as tyrosinase inhibitors for active depigmentation (Prasad et al, 2010); insecticide properties have also been associated with inhibition of insect tyrosinase (El Nagar et al, 2012).…”

Metabolic Activation of 4-Hydroxyanisole by Isolated Rat Hepatocytes

“…Metastatic melanoma cells are pigmented because active tyrosinase of the melaninsynthesizing pathway is found in melanocytes (Riley, 1991). Thus, the unique ability of melanocytes to produce melanin pigment could be exploited in an enzyme directed melanoma therapy (Jimbow et al, 1993). The selective toxicity of phenolic antimelanoma agents toward local and metastatic melanoma cells could be achieved if the phenolic agent were bioactivated by melanoma tyrosinase to form reactive o-quinones as long as the agent was not bioactivated by hepatic or renal cytochrome P450.…”

Development of radioiodine-labeled 4-hydroxyphenylcysteamine for specific diagnosis of malignant melanoma

“…Tyrosine analogues, which are tyrosinase substrates, are good candidates for developing drugs for melanoma-targeting chemotherapies [17]. 4-PCA is a better substrate for tyrosinase than 2-PCA because the structure of 4-PCA is more similar to tyrosine than 2-PCA [3,5,18].…”