title: The role of VDR and BIM in potentiation of cytarabine-induced cell death in human AML blasts.
abstract: Acute Myeloid Leukemia (AML) has grave prognosis due to aggressive nature of the disease, the toxicity of standard treatment, and overall low cure rates. We recently showed that AML cells in established culture treated with Cytarabine (AraC) and a differentiation agent combination show enhancement of AraC cytotoxicity. Here we elucidate molecular changes which underlie this observation with focus on AML blasts in primary culture. The cells were treated with AraC at concentrations achievable in clinical settings, and followed by the addition of Doxercalciferol, a vitamin D2 derivative (D2), together with Carnosic acid (CA), a plant-derived antioxidant. Importantly, although AraC is also toxic to normal bone marrow cell population, the enhanced cell kill by D2/CA was limited to malignant blasts. This enhancement of cell death was associated with activation of the monocytic differentiation program as shown by molecular markers, and the increased expression of vitamin D receptor (VDR). Apoptosis elicited by this treatment is caspase-dependent, and the optimal blast killing required the increased expression of the apoptosis regulator Bim. These data suggest that testing of this regimen in the clinic is warranted.
authors.affiliation: Department of Medicine, University of Missouri, Columbia, Missouri 65212, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Harrison
authors.affiliation: Department of Pathology & Laboratory Medicine, Rutgers New Jersey Medical School, Newark, New Jersey 07103, USA.
authors.forename: Xuening
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Missouri, Columbia, Missouri 65212, USA.
authors.forename: George P
authors.initials: GP
authors.lastname: Studzinski
mesh_terms: D045784:Abietanes / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D000072224:Bcl-2-Like Protein 11 / Q000235:genetics / Q000378:metabolism*; D003561:Cytarabine / Q000494:pharmacology*; D004357:Drug Synergism; D004872:Ergocalciferols / Q000494:pharmacology; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D034622:RNA Interference; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D020298:U937 Cells
chemical_list: D045784:Abietanes; D000072224:Bcl-2-Like Protein 11; D004872:Ergocalciferols; D018167:Receptors, Calcitriol; C579457:VDR protein, human; D003561:Cytarabine; C042533:1 alpha-hydroxyergocalciferol; C018381:salvin
keywords: Bim; acute myeloid leukemia; cytarabine; plant antioxidant; vitamin D analog