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

摘要: Background/Aims Resistance to genotoxic therapy is a characteristic feature of glioma cells. Acid sphingomyelinase (ASM) hydrolyzes sphingomyelin ceramide and glucosylceramide synthase (GCS) catalyzes metabolism. Increased levels have been suggested enhance chemotherapy-induced death cancer cells. Methods Microarray clinical data for ASM GCS in astrocytomas WHO grade II–IV were acquired from the Rembrandt database. Moreover, glioblastoma database Cancer Genome Atlas network (TCGA) was used survival patients. For vitro studies, increases achieved either by overexpression or inhibitor DL-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) human cell lines. Combinations alkylating chemotherapy irradiation overexpression, PPMP exogenous applied parental The anti-glioma effects investigated assessing proliferation, metabolic activity, viability clonogenicity. Finally, clonogenicity assessed temozolomide (TMZ)-resistant cells upon treatment with PPMP, ceramide, chemotherapy, their combinations. Results Interrogations TCGA showed better patients low expression GCS. alone led accumulation but did not activity irradiation. induced acute cytotoxicity Combined treatments additive, synergistic effects. no synergy found when TMZ-resistant treated combination TMZ irradiation. Conclusion Modulation intrinsic inhibition does