142 Vitamin D hydroxyderivatives as therapeutic agents in skin cancer

Active forms of vitamin D3, including classical 1,25(OH)2D3 and novel CYP11A1-derived hydroxyderivatives, exert their biological activity through action on vitamin D receptors (VDR) and retinoic orphan acid receptors (ROR) α and γ. Since these vitamin D analogs show antiproliferative and prodifferentiation properties, we tested their anticancer activities using human A431 squamous cell carcinoma (SCC) and murine ASZ001 carcinoma (equivalent of human basal cell carcinoma (BCC). Vitamin D3 hydroxyderivatives with or without an OH at C1α inhibited proliferation in both cell lines in a similar manner. However, colony formation and spheroid formation tests demonstrated that C1α-hydroxylation is a requirement for strong inhibitory effects vs the corresponding precursors that showed weaker or no effects. For example, secosteroids with potent anti-tumorigenic activity included 1,25(OH)2D3, 1,20(OH)2D3, 1,20,23(OH)3D3, 1,20,24(OH)3D3, 1,20,25(OH)3D3 and 1,20,26(OH)3D3, whereas, 25(OH)D3,20(OH)D3 and 20,23(OH)2D3 showed detectable, but more modest inhibitory effects. Western blot analyses revealed the expression of VDR and ROR α and γ in A431 and VDR and RORα in ASZ001 cancer cell lines. Histochemical analysis performed on human biopsies of SCC in situ, invasive SCC and BCC (n=10 for each category) showed nuclear expression of all three receptors indicating presence of several targets for vitamin D analogs bioregulation in cancer cells. Our study identified several vitamin D analogs with anti-cancer therapeutic potential and showed that SCC and BCC in vivo express several of their nuclear target receptors.