title: Novel analogs of 1,25-dihydroxyvitamin D2combined with a plant polyphenol as highly efficient inducers of differentiation in human acute myeloid leukemia cells.
abstract: 1α,25-Dihydroxyvitamin D3[1,25(OH)2D3] is known to act as a powerful differentiation inducer in various types of cancer cells, including acute myeloid leukemia (AML) cells. However, supraphysiological concentrations of 1,25(OH)2D3required to induce terminal maturation of AML cells can cause lethal hypercalcemia in vivo. Here we characterized the differentiation-inducing effects of novel double-point modified analogs of 1,25-dihydroxyvitamin D2[1,25(OH)2D2], PRI-5201 and PRI-5202 [Pietraszek et al. (2013) Steroids, 78:1003-1014], on HL60, U937 and MOLM-13 human AML cells in comparison with their direct precursors (PRI-1906 and PRI-1907, respectively) and 1,25(OH)2D3. The results demonstrated the following order of potency for the tested compounds: PRI-5202>PRI-1907>PRI-5201>PRI-1906≥1,25(OH)2D3, as determined by measuring the expression of cell surface markers of myeloid differentiation. Particularly, the sensitivity of different AML cell lines to PRI-5201 and PRI-5202 was 3-15-fold and 13-50 fold higher, respectively, compared to that of 1,25(OH)2D3. Importantly, all the analogs tested at 0.25-1nM concentrations retained the ability of 1,25(OH)2D3to cooperate with the rosemary polyphenol carnosic acid, which strongly potentiated their prodifferentiation activity in a cell type-dependent manner. These synergistic effects were associated with increased induction of the vitamin D receptor (VDR) protein expression. However, surprisingly, carnosic acid was able to significantly enhance only 1,25(OH)2D3-induced transactivation of the direct repeat 3 (DR3)-type vitamin D response element (VDRE), whereas no such cooperation was seen with 1,25(OH)2D2analogs. Furthermore, dose-response analysis revealed that 1,25(OH)2D3was more efficacious than the analogs in inducing VDRE activation. This suggests that the superior prodifferentiation activity of the analogs, as compared to 1,25(OH)2D3, may be due to their potential for enhanced activation of the differentiation-related VDRE(s) that differ from the DR3-type element tested in this study. Collectively, the results demonstrate that the new double-point modified 1,25(OH)2D2analogs are much stronger inducers of myeloid differentiation than 1,25(OH)2D3and that their efficacy can be further enhanced by combination with plant polyphenols. These combinations warrant their further mechanistic and translational exploration in AML and other types of cancer.
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Ben Gurion University of the Negev, Beer Sheva 84105, Israel.
authors.forename: Matan
authors.initials: M
authors.lastname: Nachliely
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Ben Gurion University of the Negev, Beer Sheva 84105, Israel.
authors.forename: Ehud
authors.initials: E
authors.lastname: Sharony
authors.affiliation: Department of Pharmacology, Pharmaceutical Research Institute, Warsaw 01-793, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Kutner
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Ben Gurion University of the Negev, Beer Sheva 84105, Israel. Electronic address: misha@bgu.ac.il.
authors.forename: Michael
authors.initials: M
authors.lastname: Danilenko
mesh_terms: D045784:Abietanes / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004354:Drug Screening Assays, Antitumor; D004872:Ergocalciferols / Q000138:chemical synthesis* / Q000737:chemistry*; D017930:Genes, Reporter; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology*; D017354:Point Mutation; D059808:Polyphenols / Q000737:chemistry*; D018167:Receptors, Calcitriol / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D045784:Abietanes; D000970:Antineoplastic Agents; D004872:Ergocalciferols; D059808:Polyphenols; D018167:Receptors, Calcitriol; C003564:1,25-dihydroxyergocalciferol; C018381:salvin
keywords: Acute myeloid leukemia; Analogs of 1,25-dihydroxyvitamin D(2); Carnosic acid; Cell differentiation; Vitamin D receptor