Oncology reviews
Vitamin D analogues: Potential use in cancer treatment
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.
References (77)
- et al.
The alkynylphosphonate analogue of calcitriol EM1 has potent anti-metastatic effects in breast cancer
J. Steroid Biochem. Mol. Biol.
(2015) - et al.
Efficacy of vitamin D compounds to modulate estrogen receptor negative breast cancer growth and invasion
J. Steroid Biochem. Mol. Biol.
(2003) - et al.
Vitamin D and health: the need for more randomized controlled trials
J. Steroid Biochem. Mol. Biol.
(2015) - et al.
and breast cancer: inhibition of estrogen synthesis and signaling
J. Steroid Biochem. Mol. Biol.
(2010) - et al.
The potential therapeutic benefits of vitamin D in the treatment of estrogen receptor positive breast cancer
Steroids
(2012) - et al.
Mechanistic insights of vitamin D anticancer effects
Vitam. Horm.
(2016) - et al.
Serum 25-hydroxyvitamin D levels and survival in colorectal and breast cancer patients: systematic review and meta-analysis of prospective cohort studies
Eur. J. Cancer
(2014) - et al.
Could vitamin D sufficiency improve the survival of colorectal cancer patients
J. Steroid Biochem. Mol. Biol.
(2015) - et al.
Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy
Cell
(2014) - et al.
Modulation of the vitamin D3 response by cancer-associated mutant p53
Cancer Cell
(2010)
Highly active analogs of 1alpha, 25-dihydroxyvitamin D(3) that resist metabolism through C-24 oxidation and C-3 epimerization pathways
Steroids
Blood 25-hydroxyvitamin D levels and overall mortality in patients with colorectal cancer: a dose-response meta-analysis
Eur. J. Cancer
Improved clinical outcomes associated with vitamin D supplementation during adjuvant chemotherapy in patients with HER2(+) nonmetastatic breast cancer
Clin. Breast Cancer
Vitamin D and cancer: diversity, complexity, and still a ways to go
Cancer Prev. Res. (Phila)
Calcipotriol targets LRP6 to inhibit wnt signaling in pancreatic cancer
Mol. Cancer Res.
Low serum 25-hydroxyvitamin d concentrations are associated with increased risk for melanoma and unfavourable prognosis
PLoS One
deficiency impairs rituximab-mediated cellular cytotoxicity and outcome of patients with diffuse large B-cell lymphoma treated with but not without rituximab
J. Clin. Oncol.
Vitamin D-dependent induction of cathelicidin in human macrophages results in cytotoxicity against high-grade B cell lymphoma
Sci. Transl. Med.
Vitamin D and the RNA transcriptome: more than mRNA regulation
Front. Physiol.
Circulating vitamin D levels and risk of colorectal cancer in women
Cancer Prev. Res. (Phila)
Novel vitamin D analogs as potential therapeutics: metabolism, toxicity profiling, and antiproliferative activity
Anticancer Res.
1α, 25-dihydroxyvitamin D3 inhibits esophageal squamous cell carcinoma progression by reducing IL6 signaling
Mol. Cancer Ther.
Vitamin D metabolism, molecular mechanism of action, and pleiotropic effects
Physiol. Rev.
Vitamin D deficiency and liver cancer: more than just an epidemiological association
Hepatology
A phase II study of the vitamin D analogue seocalcitol in patients with inoperable hepatocellular carcinoma
Br. J. Cancer
Superagonistic action of 14-epi-analogs of 1,25-dihydroxyvitamin D explained by vitamin D receptor-coactivator interaction
Mol. Pharmacol.
The role of vitamin D in reducing cancer risk and progression
Nat. Rev. Cancer
Inhibition of hepatocellular cancer by EB1089: in vitro and in vive study
Anticancer Res.
A phase I study of the vitamin D analogue EB 1089 in patients with advanced breast and colorectal cancer
Br. J. Cancer
Role of calcium, vitamin D, and the extrarenal vitamin D hydroxylases in carcinogenesis
Anticancer Agents Med. Chem.
Seocalcitol (EB 1089): a vitamin D analogue of anti-cancer potential Background, design, synthesis, pre-clinical and clinical evaluation
Curr. Pharm. Des.
The non-genomic actions of vitamin D
Nutrients
EB1089, a synthetic analogue of vitamin D, induces apoptosis in breast cancer cells in vivo and in vitro
Br. J. Pharmacol.
Inhibition of mouse breast tumor-initiating cells by calcitriol and dietary vitamin D
Mol. Cancer Ther.
Vitamin D suppresses leptin stimulation of cancer growth through microRNA
Cancer Res.
Vitamin D intake blood 25(OH)D levels, and breast cancer risk or mortality: a meta-analysis
Br. J. Cancer
Cited by (78)
-
Biological evaluation of combinations of tyrosine kinase inhibitors with Inecalcitol as novel treatments for human chronic myeloid leukemia
2024, Saudi Pharmaceutical Journal -
Microbial bile acid metabolite ameliorates mycophenolate mofetil-induced gastrointestinal toxicity through vitamin D3 receptor
2024, American Journal of Transplantation -
Phosphorylation of nuclear receptors: Novelty and therapeutic implications
2023, Pharmacology and Therapeutics -
Vitamin D receptor activation is a feasible therapeutic target to impair adrenocortical tumorigenesis
2022, Molecular and Cellular EndocrinologyCitation Excerpt :In line, we observed similar effects upon these cells in response to calcitriol treatment: morphology changes from flat and adherent spindle-to spherical-shaped cells. The antiproliferative effects of synthetic vitamin D3 analogs have been demonstrated in several animal models of human cancers (Duffy et al., 2017). Seocalcitol — also known as EB1089 — is a structural analog of calcitriol, that has affinity to activate IP9-type VDREs.
-
Effects of 1α,25-dihydroxyvitamin D<inf>3</inf> and tacalcitol on cell signaling and anchorage-independent growth in T98G and U251 glioblastoma cells
2022, Biochemistry and Biophysics Reports -
Role of vitamin D/VDR nuclear translocation in down-regulation of NF-κB/NLRP3/caspase-1 axis in lupus nephritis
2021, International Immunopharmacology