Amine derivatives of furocoumarin induce melanogenesis by activating Akt/GSK-3β/β-catenin signal pathway.

BACKGROUND

Melanogenesis, or the biosynthesis of melanin, plays a critical role in the pigmentation of skin, hair, and eyes. Reduced melanogenesis may lead to depigmentation conditions such as vitiligo. Psoralen, a furocoumarin derivative, is closely associated with melanogenesis, and its derivative 8-methoxypsoralen is used in psoralen and ultraviolet A therapy for pigmentation disorders. In a previous study, we synthesized a new series of amine derivatives of furocoumarin, of which 5-(morpholinomethyl)-3-phenyl-7-furo[3,2-]chromen-7-one (encoded as D206008) showed a remarkable melanogenic effect in B16 murine cells.

METHODS

In this study, we examined the effects of D206008 on the melanogenesis-related pathways in B16 cells. D206008 increased melanin production and tyrosinase (TYR) activity, as well as the mRNA and protein expression levels of the melanogenic enzymes TYR, TRP-1 and TRP-2, and the melanogenesis-related transcription factor microphthalmia-associated transcription factor (MITF) in a dose-dependent (0-100 µM) and time-dependent (0-48 hours) manner.

RESULTS

Mechanistically, D206008 inhibited β-catenin degradation by enhancing the phosphorylation of Akt and glycogen synthase kinase-3β (GSK-3β), which increased the accumulation of β-catenin in the cytoplasm. Nuclear translocation of β-catenin also increased in response to D206008 treatment.

CONCLUSION

Taken together, these data indicate that D206008 promotes melanin synthesis by stimulating the nuclear translocation of β-catenin, which activates MITF transcription and eventually melanogenesis.