Positive and negative interaction of 1,25-dihydroxyvitamin D-3 and the retinoid CD437 in the induction of human melanoma cell apoptosis

The natural ligands of the nuclear receptors vitamin D receptor (VDR) and r etinoic acid receptor (RAR), i.e., 1 alpha,25-dihydroxyvitamin D-3 (VD) and all-trans retinoic acid, have important effects on the proliferation, diff erentiation and apoptosis of a variety of malignant cells, including melano ma, The therapeutic potential of the 2 nuclear hormones can be enhanced by the use of synthetic analogues. In this study, the 2 human melanoma cell li nes WM1341 and MeWo were compared for the combined effect of VD and synthet ic retinoids. Both cell lines expressed reasonable amounts of VDR, RAR gamm a and retinoid X receptor alpha and differed only in the relative expressio n of RAR alpha and beta. From 9 functional variants of retinoids, only the RAR gamma-selective retinoid CD437 showed, in both cell lines, a significan t anti-proliferative effect. In MeWo cells, but not in WM1341 cells, VD ind uced growth arrest but showed no synergistic interaction with the effects o f CD437. In contrast, VD induced apoptosis in WM1341, but not in MeWo, cell s, CD437 was a strong inducer of apoptosis in both melanoma cell lines. Par allel treatment with CD437 and VD resulted in synergistic enhancement of ap optosis in WM1341 cells, whereas a clear decrease in induction of apoptosis in MeWo cells occurred. Our results indicate that a combined treatment of melanoma with VD and selected retinoids is promising but should be adapted to individual types of tumor. (C) 1999 Wiley-Liss, Inc.