Structure–function analysis of vitamin D2 analogs as potential inducers of leukemia differentiation and inhibitors of prostate cancer proliferation

We characterized a structure–function relationships of four analogs of vitamin D2 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 D3 (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.

► We examine a set of side-chain modified analogs of vitamin D2.
► We perform the screening of their pro-differentiating activity using HL60 cells and patient's blasts.
► The most active analogs are tested in more detailed manner using five human AML cell lines. Their ability to induce expression of CYP24A1 gene is tested.
► The anti-proliferative activity of the analogs is examined in prostate cancer cells.
► The analogs with side-chains extended by one or two carbon units are the most active in our studies.