European Journal of haematology. Accepted manuscript online: 15 October 2016. DOI: 10.1111/ejh.12818V
Paige M. Kulling, Kristine C. Olson, Thomas L. Olson, David J. Feith, Thomas P. Loughran Jr
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Commonly known for its critical role in calcium homeostasis and bone mineralization, more recently vitamin D has been implicated in haematological cancer pathogenesis and shows promise as an anti-cancer therapy. Serum levels of 25(OH)D3, the precursor to the active form of vitamin D, calcitriol, are typically lower in patients with haematological disease compared to healthy individuals. This often correlates with worse disease outcome. Furthermore, diseased cells typically highly express the vitamin D receptor (VDR), which is required for many of the anti-cancer effects observed in multiple in vivo and in vitro cancer models. In abnormal haematological cells, vitamin D supplementation promotes apoptosis, induces differentiation, inhibits proliferation, sensitizes tumor cells to other anti-cancer therapies, and reduces the production of pro-inflammatory cytokines. Although the dosage of vitamin D required to achieve these effects may induce hypercalcemia in humans, analogs and combinatorial treatments have been developed to circumvent this side effect. Vitamin D and its analogs are well tolerated in clinical trials and thus further investigation into the use of these agents in the clinic is warranted. Here we review the current literature in this field.
With the discovery of vitamin D deficiency in many haematological disorders,
understanding the role of vitamin D in the progression and treatment of such disorders is critical.
Treatment with vitamin D or its analogs has shown promise in primary patient cells and cell lines
in numerous haematological disorders and malignancies. Interestingly, the exact effects of
calcitriol vary for different cell types. In general, calcitriol suppresses pro-inflammatory cytokine
production, curtails proliferation, and inhibits antibody production in normal lymphocytes.
In malignant cells, calcitriol
- inhibits proliferation,
- induces apoptosis,
- promotes differentiation,
- sensitizes malignant cells to anti-cancer therapies, and
- enhances cell cycle arrest.
Interestingly, the exact mechanism(s) responsible for these anti-cancer effects is not yet known
and should be determined in an effort to better understand how calcitriol exerts its effects.
Furthermore, vitamin D and its analogs have been well tolerated in the clinic (7, 8) and
show promise in clinical trials for MDS (8). These studies have shown the potential of vitamin D
as a combinatorial treatment. However, the adequate serum vitamin D level in humans and
which form of vitamin D is the most appropriate to use for everyday supplementation versus
cancer treatment needs to be determined. Regardless, further investigations are warranted to
better elucidate the effects of calcitriol on abnormal cells and to determine its potential utility in
the clinical management and treatment of haematological diseases.