Radicicol and geldanamycin prevent neurotoxic effects of anti-cancer drugs on cultured embryonic sensory neurons.
Cultured dorsal root ganglion (DRG) neurons from chick embryos were extremely susceptible to the antineoplastic drugs, cisplatin, vincristine and taxol even in the presence of saturating levels of the neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3). We previously reported that a low concentration of radicicol enhanced the survival and neurite outgrowth of the embryonic sensory and sympathetic neurons, although the effect was decreased at higher doses. The neurotoxic effects of these anti-cancer drugs were completely prevented by the addition of radicicol (20 nM) to the cultures. Recent studies showed that the major intracellular target of radicicol and geldanamycin is the heat shock protein 90 (HSP90) chaperone, interfering with its function. In this study, geldanamycin at low doses (about 2 nM) also appeared to be neurotrophic on DRG neurons in the presence or absence of neurotrophins, but higher doses of geldanamycin (> 5 nM) had severe cytotoxic effects on neurons. Higher doses of radicicol (500 nM), however, still promoted neurites and prevented apoptosis of the isolated DRG neurons in the absence of neurotrophins. Geldanamycin at low doses was also found to be neuroprotective against anti-cancer drugs as shown with radicicol. Treatment of neurons with optimal doses of geldanamycin and radicicol together was cytotoxic instead of neurotrophic. These two antibiotics may share a common target to provide a trophic effect to the cultured neurons. However, different cellular effects of the two antibiotics are not easily explained. It is presumed that the novel activity might be mediated via suppression of HSP90 function, although the possibility that limited doses of these antibiotics interact with specific target molecule(s) other than HSP90 and suppress apoptosis cannot be ruled out. Present results indicate that radicicol has therapeutic potential for neurodegenerative diseases, especially for anti-cancer drug-induced sensory neuropathy.
Sano
M
M
Department of Biology, Kyoto Prefectural University of Medicine, Nishitakatsukasa, Taisyogun, Kita-ku, 603-8334, Kyoto, Japan. sano@koto.kpu-m.ac.jp
D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D016227:Benzoquinones; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002642:Chick Embryo; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology; D047029:Lactams, Macrocyclic; D007783:Lactones / Q000494:pharmacology*; D018942:Macrolides; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology; D011809:Quinones / Q000494:pharmacology*
D000970:Antineoplastic Agents; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D007783:Lactones; D018942:Macrolides; D011809:Quinones; C035359:monorden; C001277:geldanamycin