Abstract
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.
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Abbreviations
- Ara-C:
-
cytosine arabinoside
- BAF:
-
boc-aspartyl(OMe)-fluoromethylketone
- DC:
-
deoxycytidine
- DIV:
-
days in vitro
- JNK:
-
Jun N-terminal kinase
- NGF:
-
nerve growth factor
- P0:
-
postnatal day 0
- SCG:
-
superior cervical ganglion
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Acknowledgements
This work was supported by National Institutes of health Grants R37AG-12947 (EMJ), RO1NS38651 (EMJ), and NS34400 (RSF). RJ Crowder was supported by an NIH predoctoral training grant (AG00107). We thank SJ Korsmeyer (Dana-Farber Cancer Institute) for bax and bcl-2 deficient mice; PA Osborne for expert technical assistance; M Bloomgren for secretarial assistance; and members of the Johnson lab for their critical review of this manuscript. CG Besirli is a member of the Medical Scientist Training Program at Washington University School of Medicine.
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Besirli, C., Deckwerth, T., Crowder, R. et al. Cytosine arabinoside rapidly activates Bax-dependent apoptosis and a delayed Bax-independent death pathway in sympathetic neurons. Cell Death Differ 10, 1045–1058 (2003). https://doi.org/10.1038/sj.cdd.4401259
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DOI: https://doi.org/10.1038/sj.cdd.4401259
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