Suramin induced ceramide accumulation leads to apoptotic cell death in dorsal root ganglion neurons.
Suramin is an experimental antineoplastic agent that is currently being tested in clinical trials for a number of human cancers. In previous clinical trials, it has been noted that a significant percentage of patients treated with suramin develop a peripheral neuropathy. Both the cytotoxic (chemotherapeutic) and neurotoxic mechanisms of action of this compound are unknown. Evidence presented in this study suggests that both effects may be due to extensive disruption in glycolipid transport and/or metabolism. Suramin treated dorsal root ganglion cultures revealed an accumulation of the GM1 ganglioside and ceramide. Exposure of cultures to suramin, a cell permeable ceramide analog, or sphingomyelinase lead to apoptotic cell death demonstrated by electron microscopy, bis-benzimide staining and DNA laddering on gel electrophoresis. Furthermore, a significant increase in intracellular ceramide preceded cell death in suramin treated neurons. We propose that suramin induced ceramide accumulation within neurons leads to apoptotic cell death.
Gill
J S
JS
Molecular Neuroscience Program and Mayo Cancer Center, Mayo Clinic and Mayo Foundation, 1501 Guggenheim Building, 200 First Street SW, Rochester, Maine 55905, USA.gill.jagjit@mayo.edu
Windebank
A J
AJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism*; D002843:Chromatin / Q000187:drug effects / Q000648:ultrastructure; D053938:DNA Fragmentation; D004622:Embryo, Mammalian; D005727:Ganglia, Spinal / Q000166:cytology*; D006801:Humans; D007700:Kinetics; D008854:Microscopy, Electron; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009685:Nuclear Envelope / Q000187:drug effects / Q000648:ultrastructure; D051381:Rats; D013108:Sphingomyelin Phosphodiesterase / Q000494:pharmacology; D013498:Suramin / Q000494:pharmacology*; D013997:Time Factors
D002518:Ceramides; D002843:Chromatin; D013498:Suramin; D013108:Sphingomyelin Phosphodiesterase