title: Structure-function analysis of vitamin D(2) analogs as potential inducers of leukemia differentiation and inhibitors of prostate cancer proliferation.
abstract: We characterized a structure-function relationships of four analogs of vitamin D(2) with extended and branched side-chains. We tested their ability to induce differentiation of human acute myeloid leukemia (AML) cells both in vitro and ex vivo. Our experiments on five human cell lines revealed substantial differences among tested analogs. Analogs with side-chains extended by one (PRI-1906) or two carbon units (PRI-1907) displayed similar or elevated cell-differentiating activity in comparison to 1,25-dihydroxyvitamin D(3) (1,25D), whereas further extending side-chain resulted in substantially lower biological activity (PRI-1908 and PRI-1909). Similar pattern of cell-differentiating activities to that observed in human cell lines has also been shown in blast cells isolated from patients diagnosed with AML. The ability of the analogs to activate expression of CYP24A1 gene has been studied in HL60 cell line. The analog PRI-1906 activated expression of CYP24A1 similarly to 1,25D, while PRI-1907 weaker than 1,25D. In addition, the analogs PRI-1906 and PRI-1907 were able to moderately inhibit proliferation and significantly activate expression of CYP24A1 mRNA in prostate cancer cells PC-3. Finally, we examined the molecular actions triggered by these analogs and found that their biological activity was related to their ability to induce expression and nuclear translocation of VDR and C/EBPβ.
authors.affiliation: Department of Biotechnology, University of Wroclaw, Tamka, Poland.
authors.forename: H
authors.initials: H
authors.lastname: Baurska
authors.forename: A
authors.initials: A
authors.lastname: Klopot
authors.forename: M
authors.initials: M
authors.lastname: Kielbinski
authors.forename: A
authors.initials: A
authors.lastname: Chrobak
authors.forename: E
authors.initials: E
authors.lastname: Wijas
authors.forename: A
authors.initials: A
authors.lastname: Kutner
authors.forename: E
authors.initials: E
authors.lastname: Marcinkowska
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000368:Aged; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D004872:Ergocalciferols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D018167:Receptors, Calcitriol / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; D004872:Ergocalciferols; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase