Effect of 1,25(OH)2 Vitamin D3 analogs on differentiation induction and cytokine modulation in blasts from acute myeloid leukemia patients.
In acute myeloid leukemia (AML), cell proliferation and differentiation are uncoupled, causing a maturation block. Induction of terminal differentiation is a potential therapeutic strategy. 1alpha, 25(OH)2 Vitamin D3 regulates differentiation and is immunomodulatory at concentrations causing severe hypercalcemia, thus limiting its use. We investigated 1alpha, 25(OH)2 Vitamin D3 and 5 of its more potent analogs with reduced calcium resorbing activity for differentiation of blast cells from AML (FAB M1) patients, compared to TPA. Blast phenotype, p-glycoprotein expression, cytokine production, and lineage specificity were examined. The Vitamin D3 analogs had no effect on cell viability and proliferation. They induced incomplete differentiation, with increase in AP, NSE and NBT positivity of cells, but no cell sticking and spreading as observed with TPA. The analogs were more effective than the parent compound. They also inhibited the production of IL-6 and IL-8. Vitamin D3 and its analogs can induce differentiation of primary cells from AML patients in vitro, but may need to be combined with other agents for terminal differentiation of blasts and effective therapy in vivo.
Srivastava
Maya D
MD
Department of Pediatrics, Metro Health Medical Center, 2500 Metro Health Drive, Cleveland, Ohio 44109, USA.
Ambrus
Julian L
JL
D000208:Acute Disease; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002448:Cell Adhesion; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D042381:Granulocyte Precursor Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D013329:Structure-Activity Relationship; D000093242:Interleukin-6 Inhibitors
D002117:Calcitriol; D016207:Cytokines; D016209:Interleukin-8; D000093242:Interleukin-6 Inhibitors