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

Abstract

The active vitamin D hormone, 1,25-dihydroxyvitamin D 3 , exerts many physiological actions in the body, including effects on the nervous system. Studies of steroidogenesis in cells of the nervous system and elsewhere not only indicate that 1,25-dihydroxyvitamin D 3 affects steroidogenic pathways but also suggest varying responses in different cell types. For example, 1,25-dihydroxyvitamin D 3 stimulates the expression of aromatase in human glioma but not in human neuroblastoma cells or rat astrocytes. However, in astrocytes, 1,25-dihydroxyvitamin D 3 suppresses 3β-hydroxysteroid dehydrogenase and steroid 17-hydroxylase/lyase. Other studies indicate cross-talk between vitamin D signalling and signalling of oestrogens, progesterone or glucocorticoids. Reported data indicate synergistic effects of combinations of 1,25-dihydroxyvitamin D 3 and other steroid hormones on neuroinflammation, neurite outgrowth and neuroprotection. Also, dysregulation of steroid pathways affecting brain cells is found in vitamin D deficiency. Thus, several studies suggest that active vitamin D may affect steroid hormone synthesis and/or signalling in the nervous system, although the potential mechanisms for these responses remain unclear.1,25-Dihydroxyvitamin D 3 suppresses proliferation in several cell types and is therefore of interest in cancer treatment. Also, epidemiological studies associate vitamin D levels with cancer risk or outcomes. Reported data on tumours of the nervous system are mainly on glioma, a common type of brain cancer. Expression of the vitamin D receptor in glioma tumours is associated with improved survival. Several studies show that 1,25-dihydroxyvitamin D 3 and vitamin D analogues (synthetic vitamin D-like compounds) suppress proliferation and migration in human vitamin D receptor-expressing glioma cell lines. Studies on mechanisms for actions of 1,25-dihydroxyvitamin D 3 or its analogues indicate regulation of cell cycle proteins and senescence markers. These compounds also show synergism in combination with other cancer therapies treating glioma. From the data available, vitamin D analogues emerge as interesting candidates for the future improved treatment of human glioma and possibly also other cancers of the nervous system. K E Y W O R D Sglioblastoma, growth, steroid hormone, steroidogenesis, vitamin D

Calcitriol Promotes Differentiation of Glioma Stem-Like Cells and Increases their Susceptibility to Temozolomide

“…In addition, VDR-expression was found to be associated with improved overall survival [20]. Accordingly, calcitriol and/or VitD3 have been proposed as potential therapeutics for brain cancers [21,22]. Preclinical studies using differentiated GBM cell lines employed VitD3-loaded nanoparticles to induce cytotoxicity in rat glioma cells [23] and combined VitD3 with Temozolomide, leading to synergistic cytotoxicity via enhancement of autophagy [24].…”

The Effect of Vitamin D Deficiency on The Nervous System and Cardiovascular System

“…Normal levels of vitamin D are important for the nervous system. Vitamin D deficiency can cause various cancers, including glioma [5]. Vitamin D deficiency has been reported in pregnant women taking anticonvulsant drugs.…”

Impact of calcitriol and an AKT inhibitor, AT7867, on survival of rat C6 glioma cells

“…These wide effects of vitamin D on cellular processes occur by way of its specific receptor, vitamin D receptor (VDR), which also acts as a transcription factor [14,15]. In various studies it was shown that the expression rates of VDR affect the anti-neoplastic effects of calcitriol and its analogues [5,16]. In fact, the engagement of calcitriol with VDR creates a complex with retinoid X receptor (RXR).…”

“…In contrast, the inhibitors of CDKs such as p16, p21 and p27 suppress the activation of cyclin-cyclin dependent kinase (C-CDK) complex, so the lack of activation of C-CDK results in the inhibition of cell cycle progression in the G0/G1 phase. This interaction describes the mechanism by which calcitriol prevents the proliferation of tumor cells [16][17][18].…”