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A natural sleeping pill and “elixir” (longevity-promoter) called “Melatonin” is one of the first natural anti-melanogenic compounds, and originally derived from bovine pineal glands. However, currently the majority of melatonin product in the market is chemically synthesized. Since then a wide variety of anti-melanogenic compounds such as curcumin, CAPE (Caffeic Acid Phenethyl Ester), and Artepillin C (ARC) were identified in nature as well as chemically synthesized compounds such as Gleevec. These anti-melanogenic compounds share a series of interesting biological properties such as anti-cancer, anti-inflammatory, anti-ageing (longevity-promoting), immune-boosting, anti-malaria, and anti-diabetic activities. However, the precise molecular mechanism underlying their anti-melanogenic action has remained to be clarified until recently. Finally we found the first clue to understanding of the “melanogenic” signalling pathway involving the major oncogenic/ageing kinase called PAK1 (RAC/CDC42-activated kinase 1) By siRNA-based silencing of PAK1 gene in murine melanoma cell line (B16F10): (i) The major growth hormone in serum called PDGF (Platelet-Derived Growth Factor) is essential for the inducible melanogenesis, but not for the exponential growth per se, and (ii) This cytokine activates its receptor called PDGFR, a Tyr-kinase on the cell surface, and induces another cell surface receptor Tyr-kinase called EGFR (Epidermal Growth Factor Receptor), to form a heterodimer with PDGFR, activating the down-stream melanogenic/oncogenic signalling pathway involving PAK1 and eventually MITF (Microphthalmia-Associated Transcription Factor) essential for expression of Tyrosinase and its Related Protein (TRP) genes. Melatonin and many other anti-melanogenic compounds block PAK1 directly or indirectly, and eventually down-regulate tyrosinase or TRP which is essential for melanin biosynthesis from an amino acid called tyrosine.

Natural or Synthetic Anti-Melanogenic Compounds That Block the PDGFR-EGFR-PAK1-MITF-Tyrosinase Signaling Pathway