Skin complexion is one of the most recognizable phenotypes between individuals and is primarily specified by the amount and type of melanin pigment deposited in the epidermis. Persons with dark skin complexion have an increased amount of brown/black pigment known as eumelanin in their epidermis, while it is lesser in individuals with fair skin complexions. Epidermal eumelanin works as a natural sunblock and prevents incoming ultraviolet (UV) photons from penetrating the skin, thus protecting against UV mutagenesis. A good understanding of the signaling pathways and regulation of pigmentation can help develop strategies to manipulate skin pigmentation to improve UV resistance and diminish skin cancer risk.

Pharmacologic Strategies for Eumelanin Induction

NDP-MSH

It significantly increases eumelanogenesis (production of eumelanin) in humans. One study reported a 41% increase in Caucasian subjects following subcutaneous injection. NDP-MSH has been recently approved by the Food and Drug Administration for the treatment of erythropoietic protoporphyria, a rare condition characterized by UV phototoxicity.

MSH peptides

Increasing melanocortin 1 receptor (MC1R) activity in melanocytes via MSH peptide agonists can pharmacologically induce melanin production. Individuals with homozygous loss-of-function MC1R polymorphisms with red hair and poor-tanning ability may not show any benefit from peptide-induced protection from melanoma. This approach could benefit MC1R heterozygous persons and those who are at increased risk of UV-induced skin pathologies including melanoma. 

Topical forskolin

It is one of the most effective pharmacologic approaches for upregulating epidermal eumelanin levels are by topically applying forskolin, a direct activator of adenylyl cyclase, to the skin. 

SIK inhibitors

Salt-inducible kinases (SIK) have a variety of physiological roles including gut inflammation, bone resorption and formation and hepatic gluconeogenesis. SIKs counter-act a G-protein coupled receptor (GPCR)/cyclic AMP (cAMP)/protein kinase A (PKA) axis that induces microphthalmia-associated transcription factor (MITF)-dependent melanogenesis, resulting in hypopigmentation. There are three isoforms of SIK (SIK1/2/3), and the inhibitors can affect all of them. Several SIK inhibitors, like compounds ARN 3236 and pterosin B, show SIK-specific inhibitory effects. Furthermore, several pharmacological like dasatinib and bosutinib have a nonspecific inhibitory effect on SIKs through their interactions with various kinases.

Phosphodiesterase inhibition

Rolipram is a selective phosphodiesterase (PDE)-4 inhibitor that was developed as a potential antidepressant drug in the early 1990s. PDEs terminate cAMP activity via enzymatic cleavage and inactivation. Since, cAMP can cause melanin production via an MC1R-cAMP-PKA-MITF axis, inhibitors of PDEs come of translational interest. Interestingly, co-administration with forskolin can cause even greater induction of skin pigmentation, suggesting a synergistic effect. 

Depalmitoylation inhibitors

Palmitoylation of GPCRs can impact their signaling. Palmitoylation of MC1R was investigated by Chen and co-workers who recognised residue C315 as the major palmitoylation site of MC1R. They also found that the application of Palm-B, a deacylation enzyme inhibitor, decreases MC1R depalmitoylation. 

The translational potential of pharmacologic melanin induction

Increasing the amount of melanin in the skin can be used for UV health and skin cancer prevention. The development of a safe and effective means to induce epidermal eumelanin could potentially be used by individuals seeking to darken their skin (look tanner) by increasing epidermal eumelanin levels. 

Source: Kindl GH, DOrazio JA. Pharmacologic manipulation of skin pigmentation. Pigment Cell Melanoma Res. 2021;34(4):777-85.