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.