Effects of a melanogenic bicyclic monoterpene diol on cell cycle, p53, TNF-alpha, and PGE2 are distinct from those of UVB.
OBJECTIVE
Bicyclic monoterpene (BMT) diols are small-molecule compounds that mimic ultraviolet radiation (UVR) by inducing melanogenesis. The objective of this study was to compare the effects of 2,2-dimethyl-3-propanyldiol-norbornane (AGI-1140), a novel BMT diol, and ultraviolet B (UVB) on additional cellular responses.


METHODS
S91 mouse melanoma cells were treated with a range of concentrations of AGI-1140, and examined for induction of melanogenesis and nitric oxide (NO). The effect of AGI-1140 on dendrite outgrowth from human melanocytes was examined by quantitative microscopy. The effect of AGI-1140 and UVB on phosphorylation of p53 serine 15 in human keratinocytes was examined by Western blotting, while the release of tumor necrosis factor-alpha (TNF-alpha) and prostaglandin E2 (PGE2) was determined by enzyme-linked immunosorbent assay. The effects of AGI-1140 and UVB on cell cycle arrest of human melanocytes, keratinocytes, fibroblasts, and endothelial cells were compared using fluorescence-activated cell sorting.


RESULTS
Similar to UVB, AGI-1140 induced both melanogenesis and NO in melanoma cells. AGI-1140 also induced dendrite outgrowth from melanocytes, indicative of differentiation. However, whereas UVB induced G2 cell cycle arrest with phosphorylation of p53 at serine 15, AGI-1140 induced G1 cell cycle arrest without this phosphorylation. Additionally, unlike UVB, AGI-1140 did not increase the secretion of TNF-alpha or PGE2, mediators of UVB-induced immunosuppressive and inflammatory responses in the skin that may contribute to carcinogenesis.


CONCLUSIONS
This study shows that melanogenesis can be induced by AGI-1140 without many of the deleterious effects associated with UVB.
Kraus
Eliyahu
E
AGI Dermatics, 205 Buffalo Avenue, Freeport, NY 11520, USA.
Galvin
Jason W
JW
Boumakis
Stavroula
S
Boamah
Ernest K
EK
Canning
Matthew T
MT
Yarosh
Daniel B
DB
Brown
David A
DA
D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D039821:Monoterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis; D009636:Norbornanes / Q000008:administration & dosage / Q000494:pharmacology*; D012880:Skin Pigmentation / Q000187:drug effects* / Q000528:radiation effects*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014466:Ultraviolet Rays
C480566:2,2-dimethyl-3-propanyldiol-norbornane; D039821:Monoterpenes; D009636:Norbornanes; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D015232:Dinoprostone