Studies on the mechanisms of superagonistic pro-differentiating activities of side-chain modified analogs of vitamin D2

Baurska,Hanna; Marchwicka,Aleksandra; Kłopot,Anna; Kutner,Andrzej; Marcinkowska,Ewa

doi:10.3892/or.2012.1886

Studies on the mechanisms of superagonistic pro-differentiating activities of side-chain modified analogs of vitamin D2

Authors:
- Hanna Baurska
- Aleksandra Marchwicka
- Anna Kłopot
- Andrzej Kutner
- Ewa Marcinkowska
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Affiliations: Department of Biotechnology, University of Wroclaw, 50-137 Wroclaw, Poland, Pharmaceutical Research Institute, 01-793 Warszawa, Poland
Published online on: June 26, 2012 https://doi.org/10.3892/or.2012.1886
Pages: 1110-1116

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Abstract

1,25-Dihydroxyvitamin D3 (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 D2 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 pro-differentiating 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.

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