Complementary medicine treatment options for children with diffuse intrinsic pontine gliomas
by Bente Pohlmeier
Date of Examination:2024-04-11
Date of issue:2024-04-11
Advisor:Prof. Dr. Christof Kramm
Referee:PD Dr. Elisabeth Heßmann
Referee:Prof. Dr. Thomas Meyer
Persistent Address:
http://dx.doi.org/10.53846/goediss-10431
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Abstract
English
Diffuse intrinsic pontine glioma is a rare but lethal brain tumor with a median survival of eleven months after diagnosis. There has been no significant improvement in survival over the past 50 and more years despite intensive research. Therefore, parents of affected children may often use alternative complementary treatment options such as Curcumin and Boswellic acids. However, the data evaluating the effect of these compounds in diffuse intrinsic pontine glioma is limited. Therefore, the aim of the present study was to evaluate the therapeutic potential of Curcumin and Boswellic acids in an in vitro model of diffuse intrinsic pontine glioma. Curcumin reduced cell viability of pediatric high grade glioma cells in a dose dependent manner. However, no statistically significant differences in reduction of cell viability between DIPG-007 and GBM-001 cells could be detected. Furthermore, Curcumin reduced stemness and clonogenicity of pediatric high grade glioma cells and reduced levels of the stemness marker Oct4 in DIPG-007 cells. The H3K27M-mutation influences the epigenetic landscape by increasing H3K27-acetylation and reducing H3K27-trimethylation and promotes tumor growth. Treatment with Curcumin influenced the epigenetic landscape by reducing H3K27-acetylation and H4K8-acetylation hinting towards an inhibition of the histone acetyl transferase activity of the cyclic adenosine monophosphate response element binding protein binding protein by Curcumin. Remarkably, this effect was stronger in H3K27M-mutated DIPG-007 cells than in H3-wildtype GBM-001 cells suggesting that Curcumin has a stronger influence on high acetylation levels. Moreover, RNA-sequencing of DIPG-007 cells after treatment with Curcumin revealed an upregulation of genes associated with apoptosis and cell cycle arrest, leading to the assumption that Curcumin inhibits cell proliferation and mitosis. When combined with standard therapy consisting of irradiation and temozolomide Curcumin further increased their proliferation/cell viability inhibiting effect and even sensitized GBM-001 cells towards temozolomide. The three Boswellic acids derivates α-Boswellic Acid, β-Boswellic Acid, and 3-O-Acetyl-11-Keto-β-Boswellic Acid decreased cell viability in a dosage higher than 20 μM with no statistically significant differences between DIPG-007 and GBM-001 cells. However, α-Boswellic Acid and β-Boswellic Acid slightly increased cell viability in low dosages. In addition, sphere formation ability in both cell lines and colony formation ability in GBM-001 cells was not reduced after treatment with Boswellic acids. Only colony formation ability of DIPG-007 cells was reduced after treatment with Boswellic acids. Moreover, Boswellic acids did not influence the epigenetic marks H3K27-trimethylation, H3K27-acetylation, and H4K8-acetylation and 3-O-Acetyl-11-Keto-β-Boswellic Acid, the most potent Boswellic acid, did not influence gene expression in DIPG-007 cells at all, hinting towards a cytotoxic effect of Boswellic acids caused by high dosages. When combined with standard therapy, Boswellic acids further increased their cell viability reducing effect and even sensitized GBM-001 cells to temozolomide. In conclusion, Curcumin exhibits greater potential as complementary treatment option for children with diffuse intrinsic pontine glioma while the application of Boswellic acids as complementary treatment for children with diffuse intrinsic pontine glioma especially in low dosages should be considered critically.
Keywords: DIPG; Curcumin; Boswellic acid; Complementary medicine
