Induction of Skin Tanning by Subcutaneous Administration of a Potent Synthetic Melanotropin

Levine, Norman; Sheftel, Scott N.; Eytan, Ted; Dorr, Robert T.; Hadley, Mac E.; Weinrach, Jonathan C.; Ertl, Gregory; Tóth, Katalin; McGee, Daniel; Hruby, Victor J.

doi:10.1001/jama.1991.03470190078033

Cited by 176 publications

(72 citation statements)

References 21 publications

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“…For many years, there has been a wide interest in developing melanocortin analogs that can be used for "sunless tanning", to avoid the deleterious effects of UVR. Although analogs of ␣-MSH with potent pigmentary effects have been developed (27,28), yet they were not efficacious as tanning agents due to their inability to be delivered topically due to their size, and their nonselectivity for the MC1R. In this study, we have tested on cultured human melanocytes the effects of 2 N-capped tetrapeptide analogs of ␣-MSH (2 and 3) and compared them to those of the tetrapeptide Ac-His-D-Phe-Arg-Trp-NH 2 (1) and the native hormone ␣-MSH.…”

Section: Discussionmentioning

confidence: 99%

“…A melanocortin analog intended for topical use is expected to mimic the effects of ␣-MSH on human melanocytes, have potent and reversible effects, and to be selective for the MC1R. These requirements should be fulfilled in order to avoid other nonpigmentary effects of melanocortins that result from activating the four other melanocortin receptors (MC2-MC5 R; 32), as observed in subjects injected with NDP-MSH (27). It was reported that increasing the number of N-terminal capping group methylene units results in increased selectivity for the MC1R vs. MC3R or MC4R (17).…”

Section: Figurementioning

confidence: 99%

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Melanoma prevention strategy based on using tetrapeptide α‐MSH analogs that protect human melanocytes from UV‐induced DNA damage and cytotoxicity

et al. 2006

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Melanoma is the deadliest form of skin cancer, with no cure for advanced disease. We propose a strategy for melanoma prevention based on using analogs of alpha-melanocyte stimulating hormone (alpha-MSH) that function as melanocortin 1 receptor (MC1R) agonists. Treatment of human melanocytes with alpha-MSH results in stimulation of eumelanin synthesis, reduction of apoptosis that is attributable to reduced hydrogen peroxide generation and enhanced repair of DNA photoproducts. These effects should contribute to genomic stability of human melanocytes, thus preventing their malignant transformation to melanoma. Based on these findings, we synthesized and tested the effects of 3 tetrapeptide alpha-MSH analogs, Ac-His-D-Phe-Arg-Trp-NH2, n-Pentadecanoyl- and 4-Phenylbutyryl-His-D-Phe-Arg-Trp-NH2, on cultured human melanocytes. The latter two analogs were more potent than the former, or alpha-MSH, in stimulating the activity of tyrosinase, thus melanogenesis, reducing apoptosis and release of hydrogen peroxide and enhancing repair of DNA photoproducts in melanocytes exposed to UV radiation (UVR). The above analogs are MC1R agonists, as their effects were abrogated by an analog of agouti signaling protein, the physiological MC1R antagonist, and were absent in melanocytes expressing loss-of-function MC1R. Analogs, such as 4-Phenylbutyryl-His-D-Phe-Arg-Trp-NH2 with prolonged and reversible effects, can potentially be developed into topical agents to prevent skin photocarcinogenesis, particularly melanoma.

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Section: Discussionmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Melanoma prevention strategy based on using tetrapeptide α‐MSH analogs that protect human melanocytes from UV‐induced DNA damage and cytotoxicity

et al. 2006

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“…Melanocytes are neuronal in origin and they synthesize the pigment melanin in response to physical stimuli such as ultraviolet (UV) radiation or to hormones such as a-melanocyte stimulating hormone (a-MSH). Stimulation of the melanocortin 1 receptor by a-MSH stimulates cAMP production (as do agents such as forskolin and cholera toxin) and this induces melanocyte differentiation in vitro and in vivo [95,96]. In the skin, melanocytes are thought to divide very rarely, but they can be induced to proliferate in culture if provided with a complex set of signals including those from receptor and nonreceptor tyrosine kinases, PKC and -unexpectedly -the cAMP pathway.…”

Section: Melanocytes/melanomamentioning

confidence: 99%

Integrating signals between cAMP and the RAS/RAF/MEK/ERK signalling pathways

2005

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One of the hallmarks of cAMP is its ability to inhibit proliferation in many cell types, but stimulate proliferation in others. Clearly cAMP has cell type specific effects and the outcome on proliferation is largely attributed to crosstalk from cAMP to the RAS/RAF/mitogen‐activated protein kinase (MAPK) and extracellular signal‐regulated kinase (ERK) kinase (MEK)/ERK pathway. We review the crosstalk between these two ancient and conserved pathways, describing the molecular mechanisms underlying the interactions between these pathways and discussing their possible biological importance.

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“…However, some data suggest that such signals may involve a local paracrine loop occurring in the context of immediate contact between melanocytes and keratinocytes. In vivo, melanogenesis is stimulated by ultraviolet (UV) radiation (8) and by α-melanocyte-stimulating hormone (MSH) (9). In vitro, the melanogenic effects of UV radiation and of MSH can be mimicked by pharmacological agents such as forskolin, cholera toxin, and isobutylmethylxanthine.…”

mentioning

confidence: 99%

Influence of α‐melanocyte‐stimulating hormone and of ultraviolet radiation on the transfer of melanosomes to keratinocytes

et al. 2001

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The epidermal melanin unit in human skin is composed of melanocytes and keratinocytes. Melanocytes, located in the basal layer of the epidermis, manufacture melanin-loaded organelles called melanosomes. Through their dendritic processes, melanocytes distribute melanosomes to neighboring keratinocytes, where their presence confers to the skin its characteristic color and photoprotective properties. In this study, we used murine melanocytes and keratinocytes alone and in coculture to characterize the processes involved in melanosome transfer. Ultraviolet (UV) radiation induced an accumulation of melanosomes in melanocytes, whereas treatment with a-melanocyte-stimulating hormone (MSH) induced exocytosis of melanosomes accompanied by ruffling of the melanocyte membrane. We found that keratinocytes phagocytose melanosomes and latex beads equally well and that this phagocytic process was increased by exposure of keratinocytes to UV radiation or to MSH. Coculture of melanocytes and keratinocytes resulted in an increase in MSH released to the medium. Gene array analysis of MSH-treated melanocytes showed up-regulation of many genes associated with exocytosis. In our studies, we never observed cytophagocytosis of melanosome-filled processes. This result, together with the other findings, suggests that a combination of signals that increase melanosome production and release by melanocytes and that stimulate phagocytosis by keratinocytes are the most relevant mechanisms involved in skin tanning.

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Induction of Skin Tanning by Subcutaneous Administration of a Potent Synthetic Melanotropin

Cited by 176 publications

References 21 publications

Melanoma prevention strategy based on using tetrapeptide α‐MSH analogs that protect human melanocytes from UV‐induced DNA damage and cytotoxicity

Melanoma prevention strategy based on using tetrapeptide α‐MSH analogs that protect human melanocytes from UV‐induced DNA damage and cytotoxicity

Integrating signals between cAMP and the RAS/RAF/MEK/ERK signalling pathways

Influence of α‐melanocyte‐stimulating hormone and of ultraviolet radiation on the transfer of melanosomes to keratinocytes

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