TY - JOUR
T1 - α-MSH tripeptide analogs activate the melanocortin 1 receptor and reduce UV-induced DNA damage in human melanocytes
AU - Abdel-Malek, Zalfa A.
AU - Ruwe, Andrew
AU - Kavanagh-Starner, Renny
AU - Kadekaro, Ana Luisa
AU - Swope, Viki
AU - Haskell-Luevano, Carrie
AU - Koikov, Leonid
AU - Knittel, James J.
PY - 2009/10
Y1 - 2009/10
N2 - One skin cancer prevention strategy that we are developing is based on synthesizing and testing melanocortin analogs that reduce and repair DNA damage resulting from exposure to solar ultraviolet (UV) radiation, in addition to stimulating pigmentation. Previously, we reported the effects of tetrapeptide analogs of α-melanocortin (α-MSH) that were more potent and stable than the physiological α-MSH, and mimicked its photoprotective effects against UV-induced DNA damage in human melanocytes. Here, we report on a panel of tripeptide analogs consisting of a modified α-MSH core His 6-d-Phe7-Arg8, which contained different N-capping groups, C-terminal modifications, or arginine mimics. The most potent tripeptides in activating cAMP formation and tyrosinase of human melanocytes were three analogs with C-terminal modifications. The most effective C-terminal tripeptide mimicked α-MSH in reducing hydrogen peroxide generation and enhancing nucleotide excision repair following UV irradiation. The effects of these three analogs required functional MC1R, as they were absent in human melanocytes that expressed non-functional receptor. These results demonstrate activation of the MC1R by tripeptide melanocortin analogs. Designing small analogs for topical delivery should prove practical and efficacious for skin cancer prevention.
AB - One skin cancer prevention strategy that we are developing is based on synthesizing and testing melanocortin analogs that reduce and repair DNA damage resulting from exposure to solar ultraviolet (UV) radiation, in addition to stimulating pigmentation. Previously, we reported the effects of tetrapeptide analogs of α-melanocortin (α-MSH) that were more potent and stable than the physiological α-MSH, and mimicked its photoprotective effects against UV-induced DNA damage in human melanocytes. Here, we report on a panel of tripeptide analogs consisting of a modified α-MSH core His 6-d-Phe7-Arg8, which contained different N-capping groups, C-terminal modifications, or arginine mimics. The most potent tripeptides in activating cAMP formation and tyrosinase of human melanocytes were three analogs with C-terminal modifications. The most effective C-terminal tripeptide mimicked α-MSH in reducing hydrogen peroxide generation and enhancing nucleotide excision repair following UV irradiation. The effects of these three analogs required functional MC1R, as they were absent in human melanocytes that expressed non-functional receptor. These results demonstrate activation of the MC1R by tripeptide melanocortin analogs. Designing small analogs for topical delivery should prove practical and efficacious for skin cancer prevention.
KW - DNA damage
KW - DNA repair
KW - Melanocortin 1 receptor
KW - Melanoma
KW - Skin cancer
KW - α-MSH analogs
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UR - http://www.scopus.com/inward/citedby.url?scp=69449092097&partnerID=8YFLogxK
U2 - 10.1111/j.1755-148X.2009.00598.x
DO - 10.1111/j.1755-148X.2009.00598.x
M3 - Article
C2 - 19558415
AN - SCOPUS:69449092097
SN - 1755-1471
VL - 22
SP - 635
EP - 644
JO - Pigment Cell and Melanoma Research
JF - Pigment Cell and Melanoma Research
IS - 5
ER -