Oncology reviews
Vitamin D analogues: Potential use in cancer treatment

https://doi.org/10.1016/j.critrevonc.2017.02.015 Get rights and content

Highlights

  • Some epidemiological studies suggest that low levels of vitamin D are associated with an increased risk of developing specific cancers.

  • Vitamin D (calcitriol) as well as several of its synthetic analogues have been shown to inhibit tumor growth in preclinical models.

  • Some vitamin D analogues with low calcemic inducing activity have progressed to clinical trials in patients with cancer.

  • Preliminary results suggest that these vitamin D analogs have minimal toxicity, but clear evidence of efficacy remains to be shown.

Abstract

The vitamin D receptor (VDR) is a member of the thyroid-steroid family of nuclear transcription factors. Following binding of the active form of vitamin D, i.e., 1,25(OH)2D3 (also known as calcitriol) and interaction with co-activators and co-repressors, VDR regulates the expression of several different genes. Although relatively little work has been carried out on VDR in human cancers, several epidemiological studies suggest that low circulating levels of vitamin D are associated with both an increased risk of developing specific cancer types and poor outcome in patients with specific diagnosed cancers. These associations apply especially in colorectal and breast cancer. Consistent with these findings, calcitriol as well as several of its synthetic analogues have been shown to inhibit tumor cell growth in vitro and in diverse animal model systems. Indeed, some of these vitamin D analogues with low calcemic inducing activity (e.g., EB1089, inecalcitol, paricalcitol) have progressed to clinical trials in patients with cancer. Preliminary results from these trials suggest that these vitamin D analogues have minimal toxicity, but clear evidence of efficacy remains to be shown. Although evidence of efficacy for mono-treatment with vitamin D analogues is currently lacking, several studies have reported that supplementation with calcitriol or the presence of high endogenous circulating levels of vitamin D enhances response to standard therapies.

Introduction

The term vitamin D (VD) refers to a group of steroid-like molecules that includes cholecalciferol, ergocalciferol, calcidol and calcitriol (Table 1). Similar to the classical steroid hormones such as estrogens, androgens and progesterone, the active form of VD, i.e., calcitriol binds to a nuclear receptor and modulates gene expression. The best studied action of VD is the maintenance of calcium homeostasis which is accomplished by increasing calcium absorption in the intestine and decreasing its excretion by the kidneys (Feldman et al., 2014, Christakos et al., 2016, Leyssens et al., 2013). However, in addition to regulating calcium homeostasis, VD has also been implicated in several other biological processes such as induction of apoptosis, modulating the immune system, inhibiting inflammation, blocking cell proliferation and promoting cell differentiation (for review, see (Feldman et al., 2014, Christakos et al., 2016, Leyssens et al., 2013)). Thus, VD can mediate multiple and diverse effects throughout the body.

Because of its pleitrophic actions, VD has been widely investigated in several different diseases, especially cancer (Feldman et al., 2014). The aim of this article is to review the role of VD in cancer and in particular, discuss the possibility of targeting the VD receptor (VDR) for cancer treatment. Firstly, however, we briefly summarise the biosynthesis and mechanism of action of VD.

Section snippets

Biosynthesis of vitamin D

Although some VD in the body is derived from the diet, most is produced from sunlight mediated conversion of dehydrocholesterol in skin to a form of VD, known as D3 or cholecalciferol. D3 appears to have little biological activity and must undergo 2 hydroxylation reactions in order to become biologically active (Narvaez et al., 2014, Höbaus et al., 2013). The first hydroxylation, catalysed by several different members of the cytochrome P450 system, such as CYP2R1, CYP27A1, CYP2D25 and CYP2J3,

Mode of action of vitamin D

Following entry into its target tissues, calcitriol becomes attached to it’s receptor, VDR (for review, see Campbell (2014)). The VDR is a member of the nuclear family of receptors that also includes the estrogen receptor (ER), the progesterone receptor (PR), the androgen receptor (AR) and the T4/T3 receptor. While ER, PR and AR function as homodimers, VDR acts as a heterodimer, in combination with retinoid X receptor-alpha (RXRα) (Campbell, 2014). Ligand binding to the VDR-RXRα dimer leads to

Epidemiological evidence implicating vitamin D in cancer

A large number of studies have related blood levels of VD, i.e., 25-(OH)D3 to cancer incidence and survival (Feldman et al., 2014, Albanes, 2015). While individual reports differ in their conclusions, most high level evidence studies such as systematic reviews of prospective investigations followed by meta-analysis, have concluded that low blood levels are associated with an increased incidence and decreased survival. These finding particularly apply in colorectal cancer (CRC) and breast cancer

Use of 1,25(OH)2D3 and its analogues to treat cancer

Multiple studies have shown that calcitriol blocked the growth of cancer-derived cell lines in culture, while administration of calcitriol or a vitamin D-supplemented diet reduced tumor growth in a variety of animal models (Flanagan et al., 2003, Kasiappan et al., 2014, Chen et al., 2015, Murray et al., 2015, Lungchukiet et al., 2014, Swami et al., 2012, Jeong et al., 2015). The consistency of these findings across different cell lines and animal models suggest that calcitriol could potentially

Current status of calcitriol and analogues for the treatment of human cancers

Despite the promising preclinical results discussed above, there is no consistent evidence that administration of calcitriol or any of it’s analogues decreases the risk of developing cancer in humans (Feldman et al., 2014, Christakos et al., 2016, Leyssens et al., 2013, Albanes, 2015, Jorde and Grimnes, 2015, Leyssens et al., 2014). The therapeutic trials performed to date however, have had several limitations. One of the major limitations in most of these trials was that cancer was not

Mechanisms by which calcitriol or analogue may exert anti-cancer actions

Based on tumor model data, calcitriol and its analogues possess several potential activities by which they could prevent the formation or progression of cancer. These include their ability to inhibit cell proliferation, promote cell differentiation, induce apoptosis, block angiogenesis, inhibit invasion and metastasis, modulate reactive oxygen species (ROS) metabolism, regulate intracellular calcium homeostasis, prevent inflammation, promote immune response, alter metabolism, block production

Conclusion

Based on the combined data from epidemiological, cell line and animal model studies, there would appear to be a good rationale for investigating low calcemic VD analogues for cancer treatment. However, as it is unlikely that such compounds will be used alone to treat cancer, further work should investigate the combination of the VD analogues with existing systemic therapies. Of course, potential drug combinations should first be investigated in animal models and only combinations giving

Conflict of interest

MJD has received conference travel funds from Hybrigenics. JC has received research funding from Sanofi Aventis and Eisai as well as speaking honoraria from Sanofi Aventis. NO’D has also received research funding for Eisai. Other authors have no conflict of interest.

Acknowledgements

The authors wish to thank Science Foundation Ireland, Strategic Research Cluster Award (08/SRC/B1410) to Molecular Therapeutics for Cancer Ireland (MTCI), the Cancer Clinical Research Trust, The Caroline Foundation. and the BREAST-PREDICT (CCRC13GAL) programme of the Irish Cancer Society for funding this work. The funding organizations had no input into the writing of this manuscript.

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