Abstract
Despite the recent development of improved methods of treating melanoma such as targeted therapy, immunotherapy or combined treatment, the number of new cases worldwide is increasing. It is well known that active metabolites of vitamin D(3) and lumisterol (L(3)) exert photoprotective and antiproliferative effects on the skin, while UV radiation is a major environmental risk factor for melanoma. Thus, many natural metabolites and synthetic analogs of steroidal and secosteroidal molecules have been tested on various cancer cells and in animal models. In this study, we tested the anti-melanoma properties of several natural derivatives of vitamin D(3) and L(3) in comparison to 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)). A significant decrease in melanoma cell proliferation and cell mobility was observed for selected derivatives, with (25R)-27-hydroxyL(3) showing the highest potency (lowest IC50) in A375 cells but lower potency in SK-MEL-28 cells, whereas the parent L(3) failed to inhibit proliferation. The efficacy (% inhibition) by 1,24,25(OH)(3)D(3) and 1,25(OH)(2)D(3) were similar in both cell types. 1,25(OH)(2)D(3) showed higher potency than 1,24,25(OH)(3)D(3) in SK-MEL-28 cells, but lower potency in A375 cells for the inhibition of proliferation. As for 1,25(OH)(2)D(3), but not the other derivatives tested, treatment of melanoma cells with 1,24,25(OH)(3)D(3) markedly increased the expression of CYP24A1, enhanced translocation of the vitamin D receptor (VDR) from the cytoplasm to the nucleus and also decreased the expression of the proliferation marker Ki67. The effects of the other compounds tested were weaker and occurred only under certain conditions. Our data indicate that 1,24,25(OH)(3)D(3), which has undergone the first step in 1,25(OH)(2)D(3) inactivation by being hydroxylated at C24, still shows anti-melanoma properties, displaying higher potency than 1,25(OH)(2)D(3) in SK-MEL-28 cells. Furthermore, hydroxylation increases the potency of some of the lumisterol hydroxy-derivatives, as in contrast to L(3), (25R)-27(OH)L(3) effectively inhibits proliferation and migration of the human malignant melanoma cell line A375.