Updating melanoma therapy regarding melanin structure: Advances and proposals from biophysics, histochemistry and cell biology

Melanin is an ancestral biopigment with strong adaptive value and diverse functions across all phyla. In mammals, melanin appears in the skin, retinal-pigmented epithelium, central nervous system and in the malignant melanoma, one of the most aggressive and therapy-resistant tumors. Owing to the occurrence of melanin in melanomas, structural and physico-chemical properties can be considered to develop improved treatments. Several chemical structures have been suggested for melanin, but the model that best aligns with all known features, is the planar or spiral catechol/benzoquinone derivative of the porphycene ring. This model contains the 2,2'-bipyrrole motif as revealed by Ru(II)-induced luminescence, accounting for melanin's broadband light and ultrasound absorption, metal, dye and drug binding, antioxidant capacity, radical scavenging, electrical conductivity and multilayered graphite-like structure, observed by X-ray crystallography and electron microscopy. Due to this properties, endogenous melanin is an ideal target for treating melanotic melanomas by near infrared (NIR)-driven photothermal therapy (PTT). In addition to PTT with melanin itself and its complexes with red- or NIR-absorbing intercalating and redox dyes, further perspectives include PTT using mixed-valence and inclusion compounds. Recently, even more exotic approaches involve employing isotopes ¹ ⁰boron and ¹ ⁵⁷gadolinium for enhanced neutron-capture therapy, lanthanide-based up-conversion, ultrasonic-piezoelectric and tetrazine photo-explosive effects. Excited π-electrons after NIR or electrochemical production of reactive oxygen species and radicals following ultrasound absorption induce efficient thermal and/or oxidative responses, leading to tumor cell death. The ability of melanin to bind metal cations, dyes and drugs with high affinity has seminal implications for Cell Biology, Histochemistry, Pathology and Pharmacology of melanomas. Ultimately, this review explores melanin's structure as a therapeutic target, leveraging its striking biophysical, biochemical and biological properties to propose and implement new strategies for melanoma treatment.