New Insights into Pigmentary Pathways and Skin Cancer

A.J. Miller; H. Tsao

Disclosures

The British Journal of Dermatology. 2010;162(1):22-28. 

In This Article

α-Melanocyte Stimulating Hormone Agonists, Forskolin and Cyclic Adenosine Monophosphate

α-Msh secretion is used by many organisms to alter coat or skin colour. In mice, daily injections of α-Msh lead to melanogenesis within hair follicles.[47] Transdermal application of α-Msh in mice led to increased pigmentation; moreover, chemical modifications that decrease proteolytic degradation and increase binding affinity ([Nle4-D-Phe7]-α-Msh) were at least 100 times more potent.[48] Percutaneous delivery of [Nle4-D-Phe7]-α-Msh increased pigmentation at distant sites therefore demonstrating significant systemic absorption at least in mice.[49] [Nle4-D-Phe7]-α-Msh has also been tested in human volunteers and found to increase pigmentation when given by subcutaneous injection.[50] More recent work suggests that the pigmentation induced by α-Msh is indeed photoprotective. Using a cell culture system, α-Msh not only increased pigmentation but also enhanced repair of DNA photoproducts after UVR exposure.[51] In a human trial involving 65 subjects, daily subcutaneous injections of [Nle4-D-Phe7]-α-Msh for 10 days in three monthly cycles[52] led to a significant and uniform increase in pigmentation-related photoprotection. When a dosage of 3 minimum erythemal doses of UVR was administered, there was a 50% decrease in epidermal sunburn cells and a 59% decrease in thymine dimer formation. Although this delivery form is not clinically useful, it does clearly demonstrate the ability for a synthetic α-Msh analogue to provide photoprotection. While transdermal delivery works in mice, topical applications of synthetic α-Msh to minigrafts on human vitiliginous skin appeared to have no effect on local or distant pigmentation despite successful recovery of functional synthetic hormone from urine.[53]

Aside from the technical difficulties of administering peptides to humans, another major shortcoming of α-Msh is the expectation that a functional Mc1r is required to produce tanning. Cultivated melanocytes that do not respond to the growth-suppressive effects of α-Msh also fail to eumelanize.[54] In one report, α-Msh injection led to tanning in fair-skinned individuals, but no genotyping was performed. When tested on cultured human melanocytes of known MC1R genotype, no melanogenesis occurred in cells with loss of MC1R function.[51]

In direct analogy to humans, Mc1r mutations in mice lead to a yellow coat colour and an inability to tan. The major intracellular messenger used by Mc1r to induce pigmentation is cyclic adenosine monophosphate (cAMP). Forskolin directly activates adenylate cyclase thereby increasing cAMP levels and stimulates microphthalmia-associated transcription factor (Mitf) activity,[55] which recapitulates key downstream events of normal Mc1r signalling (reviewed[56]). As forskolin bypasses Mc1r, it would be expected to enhance pigmentation regardless of MC1R genotype. D'Orazio et al. demonstrated that mice expressing nonfunctional Mc1r which fail to tan in response to UVR can be stimulated to tan with daily topical application of forskolin and that the increased pigmentation had a protective effect against UVR-induced damage and carcinogenesis.[57] In a separate study, it was also found that topical application of forskolin increased the removal of CPDs and 6–4 photoproducts in human keratinocytes treated with UVB in an in vitro system.[58] As such, forskolin appears to recapitulate the natural epidermal response to UVR even in MC1R-deficient individuals by increasing their pigmentation and increasing their levels of DNA repair, but perhaps more importantly appears to do so without the need for UVR.

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