Effects of a melanogenic bicyclic monoterpene diol on cell cycle, p53, TNF-α, and PGE2 are distinct from those of UVB

Purpose: 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‐α (TNF‐α) 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‐α or PGE2, mediators of UVB‐induced immunosuppressive and inflammatory responses in the skin that may contribute to carcinogenesis. Conclusion: This study shows that melanogenesis can be induced by AGI‐1140 without many of the deleterious effects associated with UVB.