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Article

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

1
Neuroscience Center, Experimental Neurosurgery, Department of Neurosurgery, Goethe University, 60590 Frankfurt am Main, Germany
2
Faculty of Medicine, Institute of Biochemistry II, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany
3
Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, INF400, 69120 Heidelberg, Germany
4
Dr. Senckenberg Institute of Neurooncology, Goethe University Hospital, 60528 Frankfurt am Main, Germany
5
German Cancer Consortium DKTK Partner Site Frankfurt/Main, 60590 Frankfurt am Main, Germany
6
German Cancer Research Center DKFZ, 69120 Heidelberg, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally.
Academic Editor: Claudia M. Kowolik
Cancers 2021, 13(14), 3577; https://doi.org/10.3390/cancers13143577
Received: 27 June 2021 / Accepted: 13 July 2021 / Published: 16 July 2021
(This article belongs to the Special Issue Targeted Therapies for the Treatment of Glioblastoma)
Cancer cells with a stem-like phenotype that are thought to be highly tumorigenic are commonly described in glioblastoma, the most common primary adult brain cancer. This phenotype comprises high self-renewal capacity and resistance against chemotherapy and radiation therapy, thereby promoting tumor progression and disease relapse. Here, we show that calcitriol, the hormonally active form of the “sun hormone” vitamin D3, effectively suppresses stemness properties in glioblastoma stem-like cells (GSCs), supporting the hypothesis that calcitriol sensitizes them to additional chemotherapy. Indeed, a physiological organotypic brain slice model was used to monitor tumor growth of GSCs, and the effectiveness of combined treatment with temozolomide, the current standard-of-care, and calcitriol was proven. These findings indicate that further research on applying calcitriol, a well-known and safe drug, as a potential adjuvant therapy for glioblastoma is both justified and necessary.
Glioblastoma (GBM) is the most common and most aggressive primary brain tumor, with a very high rate of recurrence and a median survival of 15 months after diagnosis. Abundant evidence suggests that a certain sub-population of cancer cells harbors a stem-like phenotype and is likely responsible for disease recurrence, treatment resistance and potentially even for the infiltrative growth of GBM. GBM incidence has been negatively correlated with the serum levels of 25-hydroxy-vitamin D3, while the low pH within tumors has been shown to promote the expression of the vitamin D3-degrading enzyme 24-hydroxylase, encoded by the CYP24A1 gene. Therefore, we hypothesized that calcitriol can specifically target stem-like glioblastoma cells and induce their differentiation. Here, we show, using in vitro limiting dilution assays, quantitative real-time PCR, quantitative proteomics and ex vivo adult organotypic brain slice transplantation cultures, that therapeutic doses of calcitriol, the hormonally active form of vitamin D3, reduce stemness to varying extents in a panel of investigated GSC lines, and that it effectively hinders tumor growth of responding GSCs ex vivo. We further show that calcitriol synergizes with Temozolomide ex vivo to completely eliminate some GSC tumors. These findings indicate that calcitriol carries potential as an adjuvant therapy for a subgroup of GBM patients and should be analyzed in more detail in follow-up studies. View Full-Text
Keywords: calcitriol; vitamin D3; glioblastoma; glioblastoma stem-like cells calcitriol; vitamin D3; glioblastoma; glioblastoma stem-like cells
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MDPI and ACS Style

Gerstmeier, J.; Possmayer, A.-L.; Bozkurt, S.; Hoffmann, M.E.; Dikic, I.; Herold-Mende, C.; Burger, M.C.; Münch, C.; Kögel, D.; Linder, B. Calcitriol Promotes Differentiation of Glioma Stem-Like Cells and Increases Their Susceptibility to Temozolomide. Cancers 2021, 13, 3577. https://doi.org/10.3390/cancers13143577

AMA Style

Gerstmeier J, Possmayer A-L, Bozkurt S, Hoffmann ME, Dikic I, Herold-Mende C, Burger MC, Münch C, Kögel D, Linder B. Calcitriol Promotes Differentiation of Glioma Stem-Like Cells and Increases Their Susceptibility to Temozolomide. Cancers. 2021; 13(14):3577. https://doi.org/10.3390/cancers13143577

Chicago/Turabian Style

Gerstmeier, Julia, Anna-Lena Possmayer, Süleyman Bozkurt, Marina E. Hoffmann, Ivan Dikic, Christel Herold-Mende, Michael C. Burger, Christian Münch, Donat Kögel, and Benedikt Linder. 2021. "Calcitriol Promotes Differentiation of Glioma Stem-Like Cells and Increases Their Susceptibility to Temozolomide" Cancers 13, no. 14: 3577. https://doi.org/10.3390/cancers13143577

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