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

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.