Abstract

The active vitamin D hormone, 1,25-dihydroxyvitamin D3, is well established to inhibit cellular proliferation and induce differentiation in several cell types of the central nervous system. Indeed, a myriad of studies demonstrate the important role 1,25-dihydroxyvitamin D3 plays in maintaining a healthy brain and nervous system. This mini review will briefly summarise in vitro, in vivo, and epidemiological evidence related to the anti-proliferative and anti-cancer activities of vitamin D in hyperproliferative disorders like brain cancer. Here, we focus on the clinical application of 1,25-dihydroxyvitamin D3 and vitamin D analogues (synthetic vitamin D-like compounds) in glioblastoma treatment and discuss their potential as efficacious and tolerable adjunct therapeutic agents for patients diagnosed with this aggressive form of brain tumour.

Glioblastoma accounts for approximately 50% of all brain tumours in adults and is considered incurable due to its heterogeneity and complex pathogenesis [1]. Despite advancement of modern therapies against glioblastoma, it remains a deadly disease with poor prognosis and significantly impacts on quality of life throughout the disease course [2]. Median patient survival rates range between 14–16 months following diagnosis, and a five-year survival rate of 9.8% in patients [1], resulting in a critical public health issue. Indeed, treatment of glioblastoma remains the most challenging task in clinical oncology. Current therapeutic management involves maximal surgical resection of the tumour along with radiation and concomitant adjuvant temozolomide (TMZ) therapy [3]. However, glioblastoma has a poor response to current conventional chemotherapeutics due to varying side effects along with a relatively short half-life of TMZ-based chemotherapy (1.8 hours) [1]. 1,25-Dihydroxyvitamin D3 has emerged as a target of interest to be co-administered with different brain cancer treatments due its anti-proliferative and pro-differentiation effects in the CNS, including gliomas, and ability to cross the blood-brain-barrier [4–6]. Indeed, early studies conducted on rat glioma demonstrated that such cells respond to 1,25-dihydroxyvitamin D3 [7]. Thus, there are long-standing academic and patient-specific interests in vitamin D supplementation as a possible concomitant therapy to counteract tumour growth or reduce cancer risk.

Vitamin D and Vitamin D Analogues: Regulators of cell proliferation

Multiple in vitro studies have shown that 1,25-dihydroxyvitamin D3 promotes a proliferation-to-differentiation switch in several cell types by promoting progression through the cell cycle and subsequently driving the cells to a more differentiated phenotype [5,8]. This has been reported to occur via regulation of cell cycle protein and senescence markers [2]. The mechanisms underpinning these anti-proliferative properties elicited by 1,25-dihydroxyvitamin D3 differ across different cell types and cell lines derived from the same type of cancer [2]. Some of the known effects induced by 1,25-dihydroxyvitamin D3 are mediated through the nuclear vitamin D receptor (VDR), a transcription factor belonging to the superfamily of nuclear receptors for steroid hormones [9]. VDR is almost ubiquitously expressed throughout the human body, including the CNS, and functions by regulating over 500 genes by the ligated VDR protein’s binding to vitamin D response elements, subsequently leading to gene activation and suppression [10]. Notably, increased levels of VDR expression have been reported in different cancer types, particularly in glioblastoma versus lower-grade gliomas [11]. More recent evidence also reports overexpression of a new oncogene, MED12, in glioblastoma patients which identifies as an important mediator of VDR signalling and an attractive target for future studies in the context of glioblastoma pathogenesis [12].

It is important to note that preclinical data reveal that the levels of 1,25-dihydroxyvitamin D3 needed to significantly suppress cellular proliferation is greater than normal physiological levels [13]. For example, the most active metabolite of the 1,25-dihydroxyvitamin D3 hormone, calcitriol, exerts therapeutic effects at concentrations of 10−8 to 10−4 M [13], thus leading to serious side effects such as hypercalcaemia and possible complications during cancer treatment [2]. This has therefore led to the production of safer alternative synthetic analogues of 1,25-dihydroxyvitamin D3, including tacalcitol, calcipotriol, ML-344, EM1, CB1093, EB1089, KH1060, MC903 and MC1288, all of which have proved to be able to induce anti-tumour activity in glioblastoma without giving rise to severe hypercalcemic side effects and bioavailability issues [1]. Importantly, synthetic vitamin D analogues have been shown to interact with the VDR [14], and are also reported to suppress cellular proliferation and viability in different cancer cells [15–17]. Evidence reported by Salomón et al. showed that glioblastoma associated with VDR expression is linked with a better long-term survival of patients, thus supporting a role for VDR in glioma progression [18]. The group also investigated the role of VDR in cellular survival, migration and/or invasion (i.e., important processes in glioma progression) using human glioblastoma T98G cells, a cell line that does express VDR. They found that silencing VDR in the T98G cell line significantly increased cellular survival, whereas supplementation with calcitriol (the active 1,25-dihydroxyvitamin D3 hormone) subsequently increased VDR mRNA and protein levels and suppressed glioma cell survival [18]. Similarly, the ability of 1,25-dihydroxyvitamin D3 to suppress migration and proliferation in the T98G human glioblastoma cells was reported by Emanuelsson et al. [19]. The group also demonstrated significant suppression of proliferation and migration of T98G cells by both calcipotriol and tacalcitol, with stronger effects observed with tacalcitol [19].

Vitamin D and Vitamin D Analogues: Modulators of glioma risk and progression

Clinicians commonly use circulating vitamin D (25-hydroxyvitamin D3) to determine the index of vitamin D status in the body [20]. As defined by the Endocrine Society’s Practice Guidelines of Vitamin D, circulating 25-hydroxyvitamin D3 serum level in humans lower than 20ng/ml, from 20 to 30ng/ml, and higher than 30ng/ml are indicative of a deficiency, a relative insufficiency, and a sufficiency of vitamin D, respectively [21]. Interestingly, some epidemiological studies and clinical observations indicate a connection between vitamin D deficiency or low circulating 25-hydroxyvitamin D3 serum levels (due to limited sun exposure essential to convert cholecalciferol to Vitamin D and/or poor dietary intake) to an increased risk of developing gliomas and put forth a potential application of this vitamin as a biomarker in glioblastoma prevention or earlier prognosis, reviewed in [16,22]. Epidemiological data also suggest a higher risk of risk of brain tumours in adults to winter births [16] and comparative studies on blood bank specimens correlate higher prediagnosis serum 25-hydroxyvitamin D3 levels to lower risk of glioblastoma in men over age 56 years [23]. Glioblastoma patients with 25-hydroxyvitamin D3 serum levels greater than 30 ng/mL prior to initiation of chemotherapy and radiation demonstrate longer overall survival [16], highlighting the strong potential of supplemental vitamin D to reduce mortality in patients compared to non-users. Patients supplementing vitamin D following diagnosis of glioblastoma have also been reported to have a survival advantage [24].

Data from preclinical studies have highlighted the potential of combining the synergistic effects of 1,25-dihydroxyvitamin D3 effects with other therapeutic options for glioblastoma. For example, one study showed that TMZ and vitamin D co‑administration significantly inhibited tumour progression, concomitantly enhancing survival duration in rat glioblastoma orthotopic xenograft models, when compared to TMZ treatment alone [25]. However, despite extensive in vitro and animal studies in this field, limited small-scale clinical trials have been conducted to thoroughly evaluate the safety and efficacy of concomitant treatment with vitamin D or vitamin D on its own in the treatment of glioblastoma. A phase II clinical trial conducted by Trouillas et al., investigated adjunct alfacalcidiol (vitamin D analogue) administration in synergy with classical surgery–radiotherapy–chemotherapy treatments during treatment for malignant glioblastoma. The study reported safety of the supplementation in addition to induction of a progressive and durable regression of the tumour in some patients [26]. Ongoing phase I/II clinical trials are currently underway to determine the combinatorial effects of calcitriol with other chemotherapeutic agents on glioma and other brain tumours. In a phase I/II clinical trial, the efficacy and toxicity of long-term high-dose 1,25-dihydroxyvitamin D3 (daily dose of 4000 IU) with concurrent chemoradiotherapy containing TMZ followed by adjuvant chemotherapy containing TMZ is being investigated in newly diagnosed glioblastoma patients (ClinicalTrials.gov Identifier: NCT01181193). In another phase 1 trial, the effectiveness, and maximum tolerated doses of subcutaneous and/or oral calcitriol combined with intravenous carboplatin is being investigated in the treatment of advanced solid brain tumours (ClinicalTrials.gov Identifier: NCT00008086).

Conclusion and future perspectives

Findings based on different mouse, rodent, and human glioma cell lines report that 1,25-dihydroxyvitamin D3 and vitamin D analogues may promote cell cycle arrest, apoptosis, anti-migratory and anti-invasive effects in various types of brain cancer cells. These compounds also appear to function synergistically when combined with other cancer therapeutics for glioma. Although the preclinical and epidemiologic data are persuasive, the relevance of findings based on in vitro and preclinical studies must eventually be validated in well-designed human clinical trials to support the assertion of 1,25-dihydroxyvitamin D3 as a complementary nutritional therapy in the treatment of glioblastoma. Furthermore, future research should also focus on the development of improved vitamin D analogues, which are efficient in low doses and safe for co-administration to glioblastoma patients whose tumours express a vitamin D-responsive receptor.

References

  1. Lo CS-C, Kiang KM-Y, Leung GK-K. Anti-tumor effects of vitamin D in glioblastoma: mechanism and therapeutic implications. Laboratory Investigation. 2021 Sep 9; https://doi.org/10.1038/s41374-021-00673-8
  2. Norlin M. Effects of vitamin D in the nervous system: Special focus on interaction with steroid hormone signalling and a possible role in the treatment of brain cancer. Vol. 32, Journal of Neuroendocrinology. Blackwell Publishing Ltd; 2020. https://doi.org/10.1111/jne.12799
  3. Nachbichler SB, Schupp G, Ballhausen H, Niyazi M, Belka C. Temozolomid zur Strahlentherapie von Glioblastoma multiforme: Tägliche Gabe verbessert das Überleben. Strahlentherapie und Onkologie. 2017 Nov 1;193(11):890-6. https://doi.org/10.1007/s00066-017-1110-4
  4. Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ. Distribution of the Vitamin D receptor and 1α-hydroxylase in human brain. Journal of Chemical Neuroanatomy. 2005 Jan;29(1):21-30. https://doi.org/10.1016/j.jchemneu.2004.08.006
  5. Cui X, Gooch H, Petty A, McGrath JJ, Eyles D. Vitamin D and the brain: Genomic and non- genomic actions. Vol. 453, Molecular and Cellular Endocrinology. Elsevier Ireland Ltd; 2017. p. 131-43. https://doi.org/10.1016/j.mce.2017.05.035
  6. Diesel B, Radermacher J, Bureik M, Bernhardt R, Seifert M, Rg Reichrath J, et al. Vitamin D 3 Metabolism in Human Glioblastoma Multiforme: Functionality of CYP27B1Splice Variants, Metabolism of Calcidiol, and Effect of Calcitriol Human Cancer Biology [Internet]. Vol. 11, Clin Cancer Res. 2005. Available from: http://clincancerres.aacrjournals.org/ https://doi.org/10.1158/1078-0432.CCR-04-1968
  7. Naveilhan P, Berger F, Haddad K, Barbot N, Benabid A, Brachet P, et al. Rapid Communication Induction of Glioma Cell Death by 1,25(OH), Vitamin D,: Towards an Endocrine Therapy of Brain Tumors? Vol. 37, Journal of Neuroscience Research. 1994. https://doi.org/10.1002/jnr.490370212
  8. Garcion E, Montero-Menei CN, Wion-Barbot N, Berger F, Wion D. New clues about vitamin D functions in the nervous system [Internet]. Vol. 13, TRENDS in Endocrinology & Metabolism. 2002. Available from: http://tem.trends.com1043-2760/02/$-seefrontmatter https://doi.org/10.1016/S1043-2760(01)00547-1
  9. Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G. Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects. Physiol Rev [Internet]. 2016;96:365-408. Available from: http://www.prv.org https://doi.org/10.1152/physrev.00014.2015
  10. Orme RP, Middleditch C, Waite L, Fricker RA. The Role of Vitamin D3D3 in the Development and Neuroprotection of Midbrain Dopamine Neurons. In: Vitamins and Hormones. Academic Press Inc.; 2016. p. 273-97. https://doi.org/10.1016/bs.vh.2015.10.007
  11. Magrassi L, Bono F, Milanesi G, Butti G. Vitamin D receptor expression in human brain tumors. J Neurosurg Sci. 36(1):27-30.
  12. Srivastava S, Makala H, Sharma V, Suri V, Sarkar C, Kulshreshtha R. MED12 is overexpressed in glioblastoma patients and serves as an oncogene by targeting the VDR/BCL6/p53 axis. Cellular and Molecular Life Sciences. 2022 Feb 1;79(2). https://doi.org/10.1007/s00018-021-04056-6
  13. Beer TM, Myrthue A. Calcitriol in cancer treatment: from the lab to the clinic. Mol Cancer Ther. 2004 Mar;3(3):373-81.
  14. Brown AJ. Mechanisms for the Selective Actions of Vitamin D Analogs. In: Vitamin D. Elsevier; 2011. p. 1437-59. https://doi.org/10.1016/B978-0-12-381978-9.10075-7
  15. Chiang K-C, Yeh C-N, Hsu J-T, Chen L-W, Kuo S-F, Sun C-C, et al. MART-10, a novel vitamin D analog, inhibits head and neck squamous carcinoma cells growth through cell cycle arrest at G0/G1 with upregulation of p21 and p27 and downregulation of telomerase. The Journal of Steroid Biochemistry and Molecular Biology. 2013 Nov;138:427-34. https://doi.org/10.1016/j.jsbmb.2013.09.002
  16. Elmaci I, Ozpinar A, Ozpinar A, Perez JL, Altinoz MA. From epidemiology and neurometabolism to treatment: Vitamin D in pathogenesis of glioblastoma Multiforme (GBM) and a proposal for Vitamin D + all-trans retinoic acid + Temozolomide combination in treatment of GBM. Metabolic Brain Disease. Springer New York LLC; 2019. https://doi.org/10.1007/s11011-019-00412-5
  17. Razak S, Afsar T, Almajwal A, Alam I, Jahan S. Growth inhibition and apoptosis in colorectal cancer cells induced by Vitamin D-Nanoemulsion (NVD): involvement of Wnt/β-catenin and other signal transduction pathways. Cell & Bioscience. 2019 Dec 1;9(1):15. https://doi.org/10.1186/s13578-019-0277-z
  18. Salomón DG, Fermento ME, Gandini NA, Ferronato MJ, Arévalo J, Blasco J, et al. Vitamin D receptor expression is associated with improved overall survival in human glioblastoma multiforme. Journal of Neuro-Oncology. 2014;118(1):49-60. https://doi.org/10.1007/s11060-014-1416-3
  19. Emanuelsson I, Wikvall K, Friman T, Norlin M. Vitamin D Analogues Tacalcitol and Calcipotriol Inhibit Proliferation and Migration of T98G Human Glioblastoma Cells. Basic and Clinical Pharmacology and Toxicology. 2018 Aug 1;123(2):130-6. https://doi.org/10.1111/bcpt.13007
  20. Cashman KD, van den Heuvel EG, Schoemaker RJ, Prévéraud DP, Macdonald HM, Arcot J. 25- Hydroxyvitamin D as a Biomarker of Vitamin D Status and Its Modeling to Inform Strategies for Prevention of Vitamin D Deficiency within the Population. Advances in Nutrition: An International Review Journal. 2017 Nov 15;8(6):947-57. https://doi.org/10.3945/an.117.015578
  21. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism. 2011 Jul;96(7):1911-30. https://doi.org/10.1210/jc.2011-0385
  22. Francés MAB, Larrea L, Depiaggio M, Duque R, Vázquez G, Oset MM, et al. Vitamin D Levels in Blood and Survival in Glioblastoma. International Journal of Radiation OncologyBiologyPhysics. 2017 Oct;99(2):S188. https://doi.org/10.1016/j.ijrobp.2017.06.468
  23. Zigmont V, Garrett A, Peng J, Seweryn M, Rempala GA, Harris R, et al. Association Between Prediagnostic Serum 25-Hydroxyvitamin D Concentration and Glioma. Nutrition and Cancer. 2015 Oct 3;67(7):1120-30. https://doi.org/10.1080/01635581.2015.1073757
  24. Mulpur BH, Nabors LB, Thompson RC, Olson JJ, LaRocca R v., Thompson Z, et al. Complementary therapy and survival in glioblastoma. Neuro-Oncology Practice. 2015 Sep 1;2(3):122-6. https://doi.org/10.1093/nop/npv008
  25. Bak DH, Kang SH, Choi DR, Gil MN, Yu KS, Jeong JH, et al. Autophagy enhancement contributes to the synergistic effect of vitamin D in temozolomide based glioblastoma chemotherapy. Experimental and Therapeutic Medicine. 2016 Jun 1;11(6):2153-62. https://doi.org/10.3892/etm.2016.3196
  26. Trouillas P, Honnorat J, Bret P, Jouvet A, Gerard J-P. Redifferentiation therapy in brain tumors: long-lasting complete regression of glioblastomas and an anaplastic astrocytoma under long term 1- alpha-hydroxycholecalciferol. Vol. 51, Journal of Neuro-Oncology. 2001. https://doi.org/10.1023/A:1006437003352