Activation of the high affinity nerve growth factor receptor by two polyanionic chemotherapeutic agents: role in drug induced neurotoxicity.
Suramin is a polyanionic chemotherapeutic agent which causes severe peripheral neuropathy. The mechanisms of antineoplastic and neurotoxic activities are still poorly understood. Interference with growth factor receptor function has been suggested for suramin's chemotherapeutic function. Previous studies from our laboratory have demonstrated that suramin interfered with the function of nerve growth factor (NGF) and induced lysosomal storage defects within dorsal root ganglion neurons. Pentosan polysulfate (PPS) was used as another polyanionic agent, to compare these two cellular functions; NGF receptor interaction and disruption in glycolipid metabolism. Like suramin and NGF, PPS induced neurite outgrowth from the PC12 cell line which correlated with tyrosine phosphorylation of the high affinity NGF receptor (TrkA/gpl40) and ERK-1/MAP kinase. Ultrastructural studies of dorsal root ganglion exposed to PPS for various time periods were normal. This contrasted with suramin exposed cultures which consistently developed lamellar inclusion bodies (LIB) within 6 h. LIB formation with suramin treatment was associated with neuronal cell death, while PPS treatment did not cause any neurotoxic effects. These results indicated that PPS mimicked the effect of suramin on NGF receptors but did not cause similar accumulation of LIB. This suggested that the effect of polyanionic compounds on TrkA was not involved in LIB accumulation and subsequent induction of neurotoxicity.
Gill
J S
JS
Molecular Neuroscience Program and Mayo Cancer Center, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA. gill.jagjit@mayo.edu
Windebank
A J
AJ
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000166:cytology; D008854:Microscopy, Electron; D016501:Neurites / Q000737:chemistry / Q000187:drug effects / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000648:ultrastructure; D009498:Neurotoxins / Q000494:pharmacology; D016716:PC12 Cells; D010426:Pentosan Sulfuric Polyester / Q000737:chemistry / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D013498:Suramin / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009498:Neurotoxins; D011518:Proto-Oncogene Proteins; D017475:Receptors, Nerve Growth Factor; D010426:Pentosan Sulfuric Polyester; D013498:Suramin; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA