Carvedilol, an Adrenergic Blocker, Suppresses Melanin Synthesis by Inhibiting the cAMP/CREB Signaling Pathway in Human Melanocytes and Ex Vivo Human Skin Culture

Abstract

Catecholamines function via G protein-coupled receptors, triggering an increase in intracellular levels of 3′,5′-cyclic adenosine monophosphate (cAMP) in various cells. Catecholamine biosynthesis and the β-adrenergic receptor exist in melanocytes; thus, catecholamines may play critical roles in skin pigmentation. However, their action and mechanisms mediating melanogenesis in human skin have not yet been investigated. Therefore, we examined the potential anti-melanogenetic effect of carvedilol, a nonselective β-blocker with weak α1-blocking activities. Carvedilol reduced melanin content and cellular tyrosinase activity without compromising cellular viability in normal human melanocytes as well as in mel-Ab immortalized mouse melanocytes. Carvedilol downregulated microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2. Carvedilol treatment led to the downregulation of phosphor-cAMP response element-binding protein (CREB). Moreover, the increase in cAMP levels upon treatment with forskolin reversed the anti-melanogenic action of carvedilol. In addition, carvedilol remarkably reduced the melanin index in ultraviolet-irradiated human skin cultures. Taken together, our results indicate that carvedilol effectively suppresses melanogenesis in human melanocytes and ex vivo human skin by inhibiting cAMP/protein kinase A/CREB signaling. The anti-melanogenic effects of carvedilol have potential significance for skin whitening agents.

The Adrenergic Receptor Antagonist Carvedilol Elicits Anti-Tumor Responses in Uveal Melanoma 3D Tumor Spheroids and May Serve as Co-Adjuvant Therapy with Radiation

“…However, studies on skin carcinogenesis have suggested that the observed anti-tumor effects of carvedilol are independent of adrenergic receptor blocking, although the exact mechanism remains unknown [39]. In other studies, carvedilol has exhibited anti-oxidative and anti-proliferative activities and inhibited the PI3K/AKT and cAMP/CREB signaling pathways [17,[40][41][42]. Thus, the anti-tumor effects observed in our study may be due to the inhibition of multiple oncogenic mechanisms and need to be explored in further studies.…”

Cajanin Suppresses Melanin Synthesis through Modulating MITF in Human Melanin-Producing Cells

“…In terms of targeted modulatory pathway, natural compounds have been reported to attenuate MITF and tyrosinase transcription via restraining cAMP/CREB cascade [ 39 , 40 ]. In this study, the diminished transcription level of MITF in cajanin-treated MNT1 cells ( Figure 5 a) resulted from the down-regulation of pCREB ( Figure 7 a).…”

Recognition of Melanocytes in Immuno-Neuroendocrinology and Circadian Rhythms: Beyond the Conventional Melanin Synthesis

“…Other examples of neuroendocrine activities that exist in melanocytes are sequentially synthesizing the catecholamines, which begins with L-tyrosine, followed by generating L-DOPA, dopamine, norepinephrine, and epinephrine through classic enzymes (e.g., phenylalanine hydroxylase (PH), tyrosine hydroxylase (TH), etc.) [66][67][68][69]. The activity of PH and TH, the rate-limiting step of catecholamine biosynthesis, relies on their functional cofactor, 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6BH4) [6,9].…”