Glioma Cell Death Induced by Irradiation or Alkylating Agent Chemotherapy Is Independent of the Intrinsic Ceramide PathwayReportar como inadecuado




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Background-Aims

Resistance to genotoxic therapy is a characteristic feature of glioma cells. Acid sphingomyelinase ASM hydrolyzes sphingomyelin to ceramide and glucosylceramide synthase GCS catalyzes ceramide metabolism. Increased ceramide levels have been suggested to enhance chemotherapy-induced death of cancer cells.

Methods

Microarray and clinical data for ASM and GCS in astrocytomas WHO grade II–IV were acquired from the Rembrandt database. Moreover, the glioblastoma database of the Cancer Genome Atlas network TCGA was used for survival data of glioblastoma patients. For in vitro studies, increases in ceramide levels were achieved either by ASM overexpression or by the GCS inhibitor DL-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol PPMP in human glioma cell lines. Combinations of alkylating chemotherapy or irradiation and ASM overexpression, PPMP or exogenous ceramide were applied in parental cells. The anti-glioma effects were investigated by assessing proliferation, metabolic activity, viability and clonogenicity. Finally, viability and clonogenicity were assessed in temozolomide TMZ-resistant cells upon treatment with PPMP, exogenous ceramide, alkylating chemotherapy, irradiation or their combinations.

Results

Interrogations from the Rembrandt and TCGA database showed a better survival of glioblastoma patients with low expression of ASM or GCS. ASM overexpression or PPMP treatment alone led to ceramide accumulation but did not enhance the anti-glioma activity of alkylating chemotherapy or irradiation. PPMP or exogenous ceramide induced acute cytotoxicity in glioblastoma cells. Combined treatments with chemotherapy or irradiation led to additive, but not synergistic effects. Finally, no synergy was found when TMZ-resistant cells were treated with exogenous ceramide or PPMP alone or in combination with TMZ or irradiation.

Conclusion

Modulation of intrinsic glioma cell ceramide levels by ASM overexpression or GCS inhibition does not enhance the anti-glioma activity of alkylating chemotherapy or irradiation.



Autor: Dorothee Gramatzki, Caroline Herrmann, Caroline Happold, Katrin Anne Becker, Erich Gulbins, Michael Weller, Ghazaleh Tabatabai

Fuente: http://plos.srce.hr/



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