PMID- 11378165
OWN - NLM
STAT- MEDLINE
DCOM- 20010809
LR  - 20190726
IS  - 0028-3908 (Print)
IS  - 0028-3908 (Linking)
VI  - 40
IP  - 7
DP  - 2001 Jun
TI  - Radicicol and geldanamycin prevent neurotoxic effects of anti-cancer drugs on 
      cultured embryonic sensory neurons.
PG  - 947-53
AB  - 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.
FAU - Sano, M
AU  - Sano M
AD  - Department of Biology, Kyoto Prefectural University of Medicine, 
      Nishitakatsukasa, Taisyogun, Kita-ku, 603-8334, Kyoto, Japan. 
      sano@koto.kpu-m.ac.jp
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Neuropharmacology
JT  - Neuropharmacology
JID - 0236217
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzoquinones)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Lactams, Macrocyclic)
RN  - 0 (Lactones)
RN  - 0 (Macrolides)
RN  - 0 (Quinones)
RN  - I60EH8GECX (monorden)
RN  - Z3K3VJ16KU (geldanamycin)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*antagonists & inhibitors/toxicity
MH  - Apoptosis/*drug effects/physiology
MH  - Benzoquinones
MH  - Cell Survival/drug effects/physiology
MH  - Cells, Cultured
MH  - Chick Embryo
MH  - Enzyme Inhibitors/*pharmacology
MH  - Ganglia, Spinal/drug effects/physiology
MH  - Lactams, Macrocyclic
MH  - Lactones/*pharmacology
MH  - Macrolides
MH  - Neurons, Afferent/*drug effects/physiology
MH  - Quinones/*pharmacology
EDAT- 2001/05/30 10:00
MHDA- 2001/08/10 10:01
CRDT- 2001/05/30 10:00
PHST- 2001/05/30 10:00 [pubmed]
PHST- 2001/08/10 10:01 [medline]
PHST- 2001/05/30 10:00 [entrez]
AID - S0028390801000181 [pii]
AID - 10.1016/s0028-3908(01)00018-1 [doi]
PST - ppublish
SO  - Neuropharmacology. 2001 Jun;40(7):947-53. doi: 10.1016/s0028-3908(01)00018-1.