Glucosylceramide Synthase Inhibitors Induce Ceramide Accumulation and Sensitize H3K27 Mutant Diffuse Midline Glioma to Irradiation
H3K27M mutant (mut) diffuse midline glioma (DMG) is a lethal cancer with no effective cure. The glycosphingolipids (GSL) metabolism is altered in these tumors and could be exploited to develop new therapies. We tested the effect of the glucosylceramide synthase inhibitors (GSI) miglustat and eliglus...
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MDPI AG
2023-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/12/9905 |
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| author | Khalifa El Malki Pia Wehling Francesca Alt Roger Sandhoff Sebastian Zahnreich Arsenij Ustjanzew Carolin Wilzius Marc A. Brockmann Arthur Wingerter Alexandra Russo Olaf Beck Clemens Sommer Malte Ottenhausen Katrin B. M. Frauenknecht Claudia Paret Jörg Faber |
| author_facet | Khalifa El Malki Pia Wehling Francesca Alt Roger Sandhoff Sebastian Zahnreich Arsenij Ustjanzew Carolin Wilzius Marc A. Brockmann Arthur Wingerter Alexandra Russo Olaf Beck Clemens Sommer Malte Ottenhausen Katrin B. M. Frauenknecht Claudia Paret Jörg Faber |
| author_sort | Khalifa El Malki |
| collection | DOAJ |
| description | H3K27M mutant (mut) diffuse midline glioma (DMG) is a lethal cancer with no effective cure. The glycosphingolipids (GSL) metabolism is altered in these tumors and could be exploited to develop new therapies. We tested the effect of the glucosylceramide synthase inhibitors (GSI) miglustat and eliglustat on cell proliferation, alone or in combination with temozolomide or ionizing radiation. Miglustat was included in the therapy protocol of two pediatric patients. The effect of H3.3K27 trimethylation on GSL composition was analyzed in ependymoma. GSI reduced the expression of the ganglioside GD2 in a concentration and time-dependent manner and increased the expression of ceramide, ceramide 1-phosphate, sphingosine, and sphingomyelin but not of sphingosine 1-phosphate. Miglustat significantly increased the efficacy of irradiation. Treatment with miglustat according to dose recommendations for patients with Niemann–Pick disease was well tolerated with manageable toxicities. One patient showed a mixed response. In ependymoma, a high concentration of GD2 was found only in the presence of the loss of H3.3K27 trimethylation. In conclusion, treatment with miglustat and, in general, targeting GSL metabolism may offer a new therapeutic opportunity and can be administered in close proximity to radiation therapy. Alterations in H3K27 could be useful to identify patients with a deregulated GSL metabolism. |
| first_indexed | 2024-03-11T02:22:47Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T02:22:47Z |
| publishDate | 2023-06-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-bd10c60feb484b64aa9578c048a1bae42023-11-18T10:45:48ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-06-012412990510.3390/ijms24129905Glucosylceramide Synthase Inhibitors Induce Ceramide Accumulation and Sensitize H3K27 Mutant Diffuse Midline Glioma to IrradiationKhalifa El Malki0Pia Wehling1Francesca Alt2Roger Sandhoff3Sebastian Zahnreich4Arsenij Ustjanzew5Carolin Wilzius6Marc A. Brockmann7Arthur Wingerter8Alexandra Russo9Olaf Beck10Clemens Sommer11Malte Ottenhausen12Katrin B. M. Frauenknecht13Claudia Paret14Jörg Faber15Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, GermanyDepartment of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, GermanyDepartment of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, GermanyLipid Pathobiochemistry, German Cancer Research Center, 69120 Heidelberg, GermanyDepartment of Radiation Oncology and Radiation Therapy, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, GermanyInstitute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, GermanyLipid Pathobiochemistry, German Cancer Research Center, 69120 Heidelberg, GermanyDepartment of Neuroradiology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, GermanyDepartment of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, GermanyDepartment of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, GermanyDepartment of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, GermanyInstitute of Neuropathology, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, GermanyDepartment of Neurosurgery, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, GermanyHelmholtz-Institute for Translational Oncology Mainz (HI-TRON), 55131 Mainz, GermanyDepartment of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, GermanyDepartment of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg-University Mainz, 55131 Mainz, GermanyH3K27M mutant (mut) diffuse midline glioma (DMG) is a lethal cancer with no effective cure. The glycosphingolipids (GSL) metabolism is altered in these tumors and could be exploited to develop new therapies. We tested the effect of the glucosylceramide synthase inhibitors (GSI) miglustat and eliglustat on cell proliferation, alone or in combination with temozolomide or ionizing radiation. Miglustat was included in the therapy protocol of two pediatric patients. The effect of H3.3K27 trimethylation on GSL composition was analyzed in ependymoma. GSI reduced the expression of the ganglioside GD2 in a concentration and time-dependent manner and increased the expression of ceramide, ceramide 1-phosphate, sphingosine, and sphingomyelin but not of sphingosine 1-phosphate. Miglustat significantly increased the efficacy of irradiation. Treatment with miglustat according to dose recommendations for patients with Niemann–Pick disease was well tolerated with manageable toxicities. One patient showed a mixed response. In ependymoma, a high concentration of GD2 was found only in the presence of the loss of H3.3K27 trimethylation. In conclusion, treatment with miglustat and, in general, targeting GSL metabolism may offer a new therapeutic opportunity and can be administered in close proximity to radiation therapy. Alterations in H3K27 could be useful to identify patients with a deregulated GSL metabolism.https://www.mdpi.com/1422-0067/24/12/9905H3K27 mutant diffuse midline gliomaependymomamiglustateliglustatglycosphingolipidsGD2 |
| spellingShingle | Khalifa El Malki Pia Wehling Francesca Alt Roger Sandhoff Sebastian Zahnreich Arsenij Ustjanzew Carolin Wilzius Marc A. Brockmann Arthur Wingerter Alexandra Russo Olaf Beck Clemens Sommer Malte Ottenhausen Katrin B. M. Frauenknecht Claudia Paret Jörg Faber Glucosylceramide Synthase Inhibitors Induce Ceramide Accumulation and Sensitize H3K27 Mutant Diffuse Midline Glioma to Irradiation International Journal of Molecular Sciences H3K27 mutant diffuse midline glioma ependymoma miglustat eliglustat glycosphingolipids GD2 |
| title | Glucosylceramide Synthase Inhibitors Induce Ceramide Accumulation and Sensitize H3K27 Mutant Diffuse Midline Glioma to Irradiation |
| title_full | Glucosylceramide Synthase Inhibitors Induce Ceramide Accumulation and Sensitize H3K27 Mutant Diffuse Midline Glioma to Irradiation |
| title_fullStr | Glucosylceramide Synthase Inhibitors Induce Ceramide Accumulation and Sensitize H3K27 Mutant Diffuse Midline Glioma to Irradiation |
| title_full_unstemmed | Glucosylceramide Synthase Inhibitors Induce Ceramide Accumulation and Sensitize H3K27 Mutant Diffuse Midline Glioma to Irradiation |
| title_short | Glucosylceramide Synthase Inhibitors Induce Ceramide Accumulation and Sensitize H3K27 Mutant Diffuse Midline Glioma to Irradiation |
| title_sort | glucosylceramide synthase inhibitors induce ceramide accumulation and sensitize h3k27 mutant diffuse midline glioma to irradiation |
| topic | H3K27 mutant diffuse midline glioma ependymoma miglustat eliglustat glycosphingolipids GD2 |
| url | https://www.mdpi.com/1422-0067/24/12/9905 |
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