From epidemiology and neurometabolism to treatment: Vitamin D in pathogenesis of glioblastoma Multiforme (GBM) and a proposal for Vitamin D plus all-trans retinoic acid plus Temozolomide combination in treatment of GBM

Ilhan Elmaci, Aysel Ozpinar, Alp Ozpinar, Jennifer L. Perez, Meric A. Altinoz*

*Corresponding author for this work

Research output: Contribution to journal(Systematic) Review article peer-review

Abstract

Here we review tumoricidal efficacy of Vitamin D analogues in glioblastoma multiforme (GBM) and potential synergisms with retinoic acid and temozolomide based on epidemiological and cellular studies. Epidemiological data suggest that winter birth is associated with higher risk of GBM, and GBM debulking in the winter enhanced mortality, which may relate with lower exposure to sunlight essential to convert cholecalciferol to Vitamin D. Comparative studies on blood bank specimens revealed that higher prediagnosis levels of calcidiol are associated with lower risk of GBM in elderly men. Supplemental Vitamin D reduced mortality in GBM patients in comparison to nonusers. Expression of Vitamin D Receptor is associated with a good prognosis in GBM. Conversely, Vitamin D increases glial tumor synthesis of neutrophins NGF and NT-3, the low affinity neurotrophin receptor p75NTR, IL-6 and VEGF, which may enhance glioma growth. Antitumor synergisms between temozolomide and Vitamin D and Vitamin D with Vitamin A derivatives were observed. Hence, we hypothesize that Calcitriol + ATRA (All-Trans Retinoic Acid)+Temozolomide - CAT combination might be a safer approach to benefit from Vitamin D in the management of high-grade glial tumors. Adding acetazolomide to this protocol may reduce the risk of pseudotumor cerebri, as both Vitamin D and Vitamin A excess may cause intracranial hypertension; this approach may provide further benefit as acetazolomide also exhibits anticancer activity.

Original languageEnglish
Pages (from-to)687-704
Number of pages18
JournalMetabolic Brain Disease
Volume34
Issue number3
DOIs
Publication statusPublished - Jun 2019

Keywords

  • Glioblastoma
  • Glioma
  • Vitamin D
  • Vitamin a
  • Temozolomide
  • NERVE GROWTH-FACTOR
  • NEUROTROPHIC FACTOR GDNF
  • D-RECEPTOR EXPRESSION
  • 1,25-DIHYDROXYVITAMIN D-3
  • BRAIN-TUMOR
  • CELL-DEATH
  • C6 GLIOMA
  • PHASE-II
  • MEDROXYPROGESTERONE ACETATE
  • CANCER

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