Biochemical Characterization of Ferulic Acid and Caffeic Acid Which Effectively Inhibit Melanin Synthesis <i>via</i> Different Mechanisms in B16 Melanoma Cells

Abstract

In this study, we examined the inhibitory effects of ferulic acid and caffeic acid on melanin production using a murine B16 melanoma cell line. The mechanisms by which the two acids inhibit melanin production were investigated by evaluating their effects on the activity of tyrosinase, which is involved is the first step of melanin biosynthesis. Ferulic acid showed no toxicity against the melanoma cells at any dose, whereas caffeic acid exerted cellular toxicity at concentrations higher than 0.35 mM. Both ferulic and caffeic acids effectively inhibited melanin production in the B16 melanoma cells. Ferulic acid reduced tyrosinase activity by directly binding to the enzyme, whereas no binding was observed between caffeic acid and tyrosinase. Both ferulic acid and caffeic acid inhibited casein kinase 2 (CK2)-induced phosphorylation of tyrosinase in a dose-dependent manner in vitro. Ferulic acid was found to be a more effective inhibitor of melanin production than caffeic acid; this difference in the inhibitory efficacy between the two substances could be attributable to the difference in their tyrosine-binding activity. Our analysis revealed that both substances also inhibited the CK2-mediated phosphorylation of tyrosinase.

Natural and Bioinspired Phenolic Compounds as Tyrosinase Inhibitors for the Treatment of Skin Hyperpigmentation: Recent Advances

“…At present, though a wide range of tyrosinase inhibitors from natural and synthetic sources have been reported, only a few of them, in addition to being effective, are known as safe compounds. No significant advances concerning toxicity issues of tyrosinase inhibitors seem to emerge from the literature survey carried out for this review, the relevant papers just reporting the results of in vitro cytotoxicity experiments [49,52,75,81,95,126,129,[131][132][133]136,137,147,163,[176][177][178]184,185,192,198,202,203,207,210,212,214,215,239,240,242,245] and only a few of in vivo experiments on zebrafish [130,206,209]. Therefore, it is essential to examine the efficacy and safety of inhibitors by checking e.g., whether or not the candidate inhibitor is substrate of tyrosinase being modified on exposure to the enzyme.…”

“…As an example, in silico analysis showed that the flavonoids spinosin and swertiajaponin act as competitive inhibitors of the enzyme by binding to the active site through hydrogen bonding and hydrophobic interactions [212,214], as is the case also for condensed tannins from different sources Of course, care should be taken when cellular or in vivo models are considered, since several alternative or additional biochemical mechanisms can be operative, involving e.g., tyrosinase expression and interference with the complex signaling pathways in melanogenesis, which could result in melanin reduction as well. As an example, it has been reported that both ferulic and caffeic acid inhibited melanin production in B16 melanoma cells, but ferulic acid reduced tyrosinase activity by directly binding to the enzyme, whereas no binding was observed in the case of caffeic acid [177]. Apart from the direct inhibition of tyrosinase activity, the anti-melanogenic activity of resorcinol in B16F10 cells has been attributed to the inhibition of cAMP signaling and activation of p38 MAPK [179].…”

Biochemical and cellular mechanism of protein kinase CK2 inhibition by deceptive curcumin

“…Ferulic acid has been proposed as a potential treatment for Alzheimer’s disease, cancer and cardiovascular diseases . Inhibition of CK2 by ferulic acid was already observed in kinase assay using tyrosinase as substrate . Among other activities, vanillin was found to induce apoptosis in cancer cells by inhibiting NF‐κB phosphorylation and activation .…”

Calebin-A, a Curcuminoid Analog Inhibits α-MSH-Induced Melanogenesis in B16F10 Mouse Melanoma Cells

“…The structure of CBA does not incorporate the beta-diketone group characteristic of the structure of the curcuminoid curcumin but rather retains the structure of an ester of ferulic acid, a metabolite of curcumin. Ferulic acid has been known to regulate melanogenesis dependent on concentration, conflicting reports showed that ferulic acid can induce melanogenesis [38] or inhibit melanogenesis [39]. CBA has a Michael acceptor group (C=C double bond) similar to curcumin.…”