Retinoic Acid receptor-gamma-selective retinoids exert antiproliferative effects on human-melanoma cell-growth...

Malignant melanoma is a cancer with dramatically increasing incidence and mortality. Alternative approaches for therapy of disseminated malignant melanoma are urgently needed. In order to develop new alternatives for therapy of metastatic melanoma, we tested the biological activity of eight synthetic retinoids with high affinity and/or selectivity for the retinoic acid receptors (RAR) alpha, beta and gamma in comparison to all-trans retinoic acid, arotinoid acid and CD 367 in four human melanoma cell lines. The melanoma cell growth was not affected by most retinoids tested, however, two of the synthetic substances with high RAR-gamma selectivity (CD 437 and CD 2325) showed a dose-dependent antiproliferative effect on all melanoma cell lines tested with IC50 values between 10(-6) and 10(-7) M. A structurally closely related compound, CD 2398, lacking the carboxyl-terminal group and therefore exhibited no RAR-binding did not change melanoma cell growth behaviour. We demonstrate the expression of RAR-alpha, RAR-beta and RAR-gamma, in four human melanoma cell lines by polymerase chain reaction. Taken together, these results suggest that binding and stimulation of the RAR-gamma receptor might be a major factor in growth inhibition of human melanoma cell by retinoids in vitro. Although several of the compounds altered the cell surface expression of defined melanocytic differentiation markers, the correlation to changes in melanin content was poor. Furthermore, five out of eight retinoids modulated HLA-DR expression on human melanoma cells. The potent growth inhibitory effect of the RAR-gamma selective retinoids as well as their immunomodulating capacities opens an interesting alternative for new antiproliferative and immunomodulatory strategies in the therapy of metastatic melanoma.