Hyperpigmentation in S91 Cells Co-cultured with Human Dermal Fibroblasts by Prostaglandin Fp Receptor Agonists

Abstract

Abstract: : Purpose: Latanoprost, an FP receptor agonist used for glaucoma treatment, has been reported to increase pigment formation in the iris. In an attempt to understand the mechanism of drug-related hyperpigmentation and a possible indirect effect of prostaglandin FP receptor agonists on melanogenesis in mouse S91 melanoma cells, a transwell co-culture assay was established to evaluate this phenomenon. Methods: S91 cells were cultured in 6-well plates and human dermal fibroblasts, which express FP receptors and functionally respond to FP receptor agonist stimulation, were cultured in a transwell format. The cells were stimulated with test compounds for 4 days. The activity of tyrosinase, an important enzyme involved in melanin formation, and proliferation of S91 cells were investigated. Results: The experiments showed that the FP receptor agonists latanoprost-acid and PGF_2α were more effective in increasing tyrosinase activity in S91 cells cultured with fibroblasts than in S91 cells cultured alone. Neutral, non-acidic lipids, such as the synthetic prostamide bimatoprost, AGN 190910 (PGF_2α-1-alcohol), AGN 191129 (PGF_2α-1-methylether) and the endocannabinoid/endovanilloid anandamide, exhibited no stimulatory effect on tyrosinase under the same conditions. Conclusions: The studies indicate that FP receptor agonists probably act on the dermal fibroblast FP receptors and indirectly stimulate the tyrosinase enzyme in S91 cells. Neutral lipids, including bimatoprost, did not stimulate tyrosinase activity in S91 cells co-cultured with human dermal fibroblasts. An indirect stimulation of pigment formation may be the mechanism by which latanoprost causes iris darkening. The lack of effect of bimatoprost in this system may explain why this glaucoma medication has virtually no effect on iris color.

Keywords: eicosanoids • iris • melanocytes