Sphingolipids

Opálka, Lukáš; Schlicker, Lisa; Sandhoff, Roger

doi:10.1002/9783527836512.ch15

Cited by 1 publication

(1 citation statement)

References 267 publications

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“…Liquid-chromatography-coupled tandem mass spectrometric analysis of sphingolipids was performed on an Aqcuity I class UPLC (Waters, Milford, MA, USA) coupled through electrospray ionization (ESI) to a triple-quadrupole-like tandem mass spectrometer (Xevo TQ-S, Waters, Milford, MA, USA) according to previous publications [ 23 , 78 ]. As described, GD2 was analyzed with an Anionoic Polar Pesticide column (5 µm, 150 mm × 2.1 mm, Waters) in MRM mode [ 23 ], whereas all other sphingolipids were separated on a reversed-phase CSH C18 column (2.1 mm × 100 mm; 1.7 μm, Waters) in MRM mode [ 78 , 79 ]. In positive electrospray ionization mode protonated molecular ions of S1P, Cer, Cer1P, HexCer (likely GlcCer), and Hex2Cer (likely LacCer), GM3 and GD3 ions were detected with transitions to the product ion m/z 264 and protonated molecular HexNAc-Hex2Cer (likely GA2), GM2, GD2, Tetraosylceramide (likely GA1 and Gb4Cer), and GM1 ions to the product ion m/z 204.…”

Section: Methodsmentioning

confidence: 99%

Glucosylceramide Synthase Inhibitors Induce Ceramide Accumulation and Sensitize H3K27 Mutant Diffuse Midline Glioma to Irradiation

El Malki,

Wehling,

Alt

et al. 2023

IJMS

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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.

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