Suramin induced ceramide accumulation leads to apoptotic cell death in dorsal root ganglion neurons

Abstract

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 GM 1 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.

Medication-induced peripheral neuropathy

“…Suramin-treated neuronal cultures have shown accumulation of GM1 gangliosides and ceramide, as well as other gangliosides [31]. Ceramide levels, an important mediator of programmed cell death, are boosted intracellularly in cultured neurons treated with suramin, suggesting a possible ceramide-induced apoptotic mechanism of neurotoxicity [31]. Interestingly, a parallel mechanism may underlie a dominant form of hereditary sensory and autonomic neuropathy type I, in which a defect in ceramide synthesis raises ceramide levels, possibly triggering apoptosis.…”

“…In patients with plasma levels of suramin over 350 µg/mL, the incidence of neuropathy appears to be approximately 15%, but may be as high as 40% [30]. Suramin-treated neuronal cultures have shown accumulation of GM1 gangliosides and ceramide, as well as other gangliosides [31]. Ceramide levels, an important mediator of programmed cell death, are boosted intracellularly in cultured neurons treated with suramin, suggesting a possible ceramide-induced apoptotic mechanism of neurotoxicity [31].…”

“…Suramin also inhibits DNA polymerase, as well as several growth factors, including NGF, and appears to compete with NGF for high-affinity binding sites in cells. This growth factor inhibition is proposed as a possible neurotoxic mechanism [31,32]. Increasing suramin doses inhibits NGF-specific binding, and conversely high-dose NGF can block suramin toxicity on DRG neurons [32].…”

Rejuvenating Sirtuins: The Rise of a New Family of Cancer Drug Targets

“…Suramin has anticancer activity and has been studied in clinical trials [71]. However, it is still unclear to which extent such activity is due to sirtuin inhibition or, instead, to other modes of action, such as adenosine receptor activation or ceramide accumulation [72]. The optimization of the suramin scaffold led to NF675 ( 13 , Fig.…”

Book Review: Cell Death in the Peripheral Nervous System: Potential Rescue Strategies

“…These include ionizing radiation, growth factor withdrawal, hydrogen peroxide, heat shock, chemotherapeutic drugs (such as suramin and daunorubicin), dexamethasone (a synthetic glucocorticoid hormone), and 1,25-dihydroxyvitamin D (Cifone and others 1999;Gill and Windebank 1998b;Hofmann and Dixit 1998). Ceramide levels may also be increased in response to extracellular ligand-receptor binding including Fas ligand and the tumor necrosis factor ligand.…”