title: Melanoma prevention strategy based on using tetrapeptide alpha-MSH analogs that protect human melanocytes from UV-induced DNA damage and cytotoxicity.
abstract: 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.
authors.affiliation: Department of Dermatology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, Ohio 45267-0592, USA. abdelmza@email.uc.edu
authors.forename: Zalfa A
authors.initials: ZA
authors.lastname: Abdel-Malek
authors.forename: Ana Luisa
authors.initials: AL
authors.lastname: Kadekaro
authors.forename: Renny J
authors.initials: RJ
authors.lastname: Kavanagh
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Todorovic
authors.forename: Leonid N
authors.initials: LN
authors.lastname: Koikov
authors.forename: Joseph C
authors.initials: JC
authors.lastname: McNulty
authors.forename: Pilgrim J
authors.initials: PJ
authors.lastname: Jackson
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Millhauser
authors.forename: Sandy
authors.initials: S
authors.lastname: Schwemberger
authors.forename: George
authors.initials: G
authors.lastname: Babcock
authors.forename: Carrie
authors.initials: C
authors.lastname: Haskell-Luevano
authors.forename: James J
authors.initials: JJ
authors.lastname: Knittel
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D004249:DNA Damage; D006801:Humans; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects*; D008545:Melanoma / Q000517:prevention & control*; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D012878:Skin Neoplasms / Q000517:prevention & control*; D014466:Ultraviolet Rays; D000521:alpha-MSH / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016588:Anticarcinogenic Agents; D009842:Oligopeptides; D010446:Peptide Fragments; D000521:alpha-MSH