Effects of Vitamin D Derivatives on Differentiation, Cell Cycle, and Apoptosis in Hematological Malignancies

George P. Studzinski, Elzbieta Gocek, Frederick Coffman, Michael Danilenko

Research output: Chapter in Book/Report/Conference proceedingChapter

2 Scopus citations

Abstract

The physiological form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), has a role in normal hematopoiesis, enhancing monocyte-macrophage differentiation. It also has antiproliferative and prodifferentiation effects against various myeloid leukemia cell lines and acute myeloid leukemia (AML) blasts ex vivo. Nevertheless, hematopoiesis in mice with vitamin D receptor (VDR) deletion is essentially normal, indicating that in mammals the vitamin D pathway appears to have a nonessential but perhaps a contributory role in blood formation. This chapter reviews the general mechanisms by which vitamin D derivatives (VDDs) can drive cell differentiation, the associated cell cycle traverse arrest, and alter cell survival. However, in vivo these activities of 1,25(OH)2D3 require supraphysiological levels of 1,25(OH)2D3. The important distinctions between different mechanisms of 1,25(OH)2D3-induced differentiation that are cell type and cell context-specific and the different pathways that participate in 1,25(OH)2D3-induced signal propagation are described here. Clinical trials with 1,25(OH)2D3 have been performed for the treatment of preleukemia/myelodysplastic syndrome and AML, but the doses effective in vitro caused hypercalcemia in vivo. However, numerous vitamin D analogs have been synthesized, which, in model systems, have reduced calcemic activity but have increased ability to induce cell differentiation and to inhibit proliferation of leukemic cells. Perhaps the available or new analogs combined with other differentiating or antiproliferative agents, each working through different pathways, will demonstrate synergistic activity and offer improved therapy for AML.

Original languageEnglish (US)
Title of host publicationHealth, Disease and Therapeutics
PublisherElsevier Inc.
Pages761-799
Number of pages39
Volume2
ISBN (Electronic)9780128099650
ISBN (Print)9780128099643
DOIs
StatePublished - Dec 14 2017

All Science Journal Classification (ASJC) codes

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Keywords

  • Apoptosis
  • Cell cycle control
  • Clinical trials
  • Differentiation
  • Leukemia
  • Signal transduction
  • Vitamin D

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