Studies on the mechanisms of superagonistic pro-differentiating activities of side-chain modified analogs of vitamin D 2

Abstract

1,25-Dihydroxyvitamin D 3 (1,25D) is implicated in many cellular functions including cell proliferation and differentiation, thus, exerting potential antitumor effects. A major limitation for therapeutic use of 1,25D are its potent calcemic and phosphatemic activities. Therefore, synthetic analogs of 1,25D for use in anticancer therapy should retain cell differentiating potential, with calcemic activity being reduced. Previously, we described pro-differentiating effects of vitamin D 2 analogs with extended and branched side-chains. Analogs with side-chains extended by a pair of one (PRI-1906) or two carbon units (PRI-1907) displayed elevated cell-differentiating activity towards some acute leukemia cell lines (AML) in comparison to 1,25D. In this study, the potential mechanism of this superagonistic activity of the analogs was addressed. At first, possible differences in the expression of CYP24A1, a major catabolizing enzyme for vitamin D compounds and resulting differences in the degradation of analogs were investigated. In addition, interactions of the analogs with vitamin D receptor (VDR) and resulting activation of CCAAT-enhancer-binding protein β (C/EBPβ) were studied. The results obtained show that superagonistic prodifferentiating activities of analogs PRI-1906 and PRI-1907 do not seem to be caused by their altered catabolism, but most probably by altered interactions with VDR and resulting downstream proteins.