Cytosine arabinoside rapidly activates Bax-dependent apoptosis and a delayed Bax-independent death pathway in sympathetic neurons

Cell Death Differ. 2003 Sep;10(9):1045-58. doi: 10.1038/sj.cdd.4401259.


Cytosine arabinoside (ara-C) is a nucleoside analog used in the treatment of hematologic malignancies. One of the major side effects of ara-C chemotherapy is neurotoxicity. In this study, we have further characterized the cell death induced by ara-C in sympathetic neurons. Similar to neurons undergoing trophic factor deprivation-induced apoptosis, ara-C-exposed neurons became hypometabolic before death and upregulated c-myb, c-fos, and Bim. Bax deletion delayed, but did not prevent, ara-C toxicity. Neurons died by apoptosis, indicated by the release of mitochondrial cytochrome-c and caspase-3 activation. p53-deficient neurons demonstrated decreased sensitivity to ara-C, but neither p53 nor multiple p53-regulated genes were induced. Mature neurons showed increased ara-C resistance. These results demonstrate that molecular mechanisms underlying ara-C-induced death are similar to those responsible for trophic factor deprivation-induced apoptosis. However, substantial differences in neuronal death after these two distinct stress stimuli exist since ara-C toxicity, unlike the developmental death, can proceed in the absence of Bax.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / toxicity*
  • Apoptosis*
  • Caspase 3
  • Caspases / metabolism
  • Cell Differentiation
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cytarabine / toxicity*
  • Cytochromes c / metabolism
  • Dose-Response Relationship, Drug
  • Female
  • Gene Deletion
  • Genes, p53
  • Kinetics
  • Male
  • Mice
  • Mitochondria / metabolism
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-bcl-2*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Superior Cervical Ganglion / cytology*
  • Up-Regulation
  • bcl-2-Associated X Protein


  • Antimetabolites, Antineoplastic
  • Bax protein, mouse
  • Bax protein, rat
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2-Associated X Protein
  • Cytarabine
  • Cytochromes c
  • Casp3 protein, mouse
  • Casp3 protein, rat
  • Caspase 3
  • Caspases