Isoquercitrin induces melanogenesis in B16F10 melanoma cells and zebrafish via the p38 and PKA/CREB signaling pathways: an experimental study

Abstract

Background: Isoquercitrin (IQ), a flavonoid with anticancer, antioxidant, anti-inflammatory, and antiallergic properties, exhibits dual effects on B16F10 melanoma cells by suppressing cell viability and inducing hyperpigmentation. This study investigated the molecular mechanisms underlying IQ-induced melanogenesis in vitro and in vivo, highlighting the potential of IQ in the treatment of vitiligo.Methods: B16F10 melanoma cells and zebrafish were treated with various IQ concentrations and melanogenesis was evaluated using western blotting, a tyrosinase activity assay, and microscopic observation. In addition, signaling pathway modulators and IQ were used to confirm the signaling pathways involved in IQ-induced melanogenesis.Results: IQ treatment of B16F10 melanoma cells enhanced tyrosinase activity and upregulated melanogenesis-associated proteins, including microphthalmia-associated transcription factor and tyrosinase, via the p38 and protein kinase A (PKA)/cyclic AMP response element-binding protein (CREB) signaling pathways. Cotreatment with pathway-specific inhibitors (SB203580 for p38 and H89 for PKA/CREB) attenuated melanogenesis, whereas forskolin (a PKA/CREB activator) enhanced melanogenesis, confirming the involvement of these signaling pathways. In zebrafish, IQ treatment significantly increased melanophore production in the dorsal region following hypopigmentation induction with 1-phenyl-2-thiourea. Similar to that in B16F10 melanoma cells, SB203580 and H89 suppressed IQ-induced pigmentation, whereas forskolin enhanced it.Conclusion: These findings demonstrate that IQ promotes melanogenesis in vitro and in vivo through activation of the p38 and PKA/CREB signaling pathways, supporting its potential as a therapeutic agent for vitiligo.