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

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.

Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

“…Neuronal cell death in response to DNA damage in vitro or prion expression in vivo can occur in a fast Bax-dependent or slow Bax-independent manner, paralleling our findings with neomycin-and gentamicin-induced hair cell death (Besirli et al 2003;Li et al 2007). Importantly, the slow form of Bax-independent death induced by DNA damage involved p53 activity (Besirli et al 2003).…”

“…Importantly, the slow form of Bax-independent death induced by DNA damage involved p53 activity (Besirli et al 2003). p53 can also interact directly with pro-survival and pro-cell death Blc2 family members to activate mitochondrial-associated cell death path-ways (Mihara et al 2003;Chipuk et al 2004;Moll et al 2005;Han et al 2010).…”

“…Through this route, Bax is closely associated with caspase activation and classical apoptosis (reviewed in van Delft and Huang 2006;Tait and Green 2010). However, Bax is also necessary for mitochondrial changes and activation of downstream cell death pathways in a caspase-independent manner (Middleton et al 2000;Besirli et al 2003;Cheung et al 2005). Bcl2 family members have been linked to aminoglycoside ototoxicity in rodent models and noise-induced hearing loss (Cunningham et al 2004;Vicente-Torres and Schacht 2006;Yamashita et al 2008;Pfannenstiel et al 2009). p53 is best recognized as a transcription factor with hundreds of downstream targets, playing a central role in DNA repair, cell cycle regulation, and cell death (reviewed in Pietsch et al 2008;Levine and Oren 2009).…”

Endoplasmic reticulum stress-induced apoptosis requires bax for commitment and Apaf-1 for execution in primary neurons

“…27 As a result, Bax-deficient sympathetic neurons are resistant to death following NGF deprivation and DNA damage. 28,29 Therefore, we examined whether Bax deficiency alone was capable of preventing ER stress-induced apoptosis in sympathetic neurons. Our results show that Bax-deficient neurons remained viable long after the wild-type neurons had undergone apoptosis in response to both TU and TG ( Figure 4a and b, Supplementary Figure 4).…”

“…These results are in contrast to NGF deprivation, in which commitment to death occurs coincident with the mitochondrial release of cytochrome c. 31 In this respect, ER stress appears similar to DNA damage which also commits neurons to die early, before cytochrome c release. 29 As DNA damage commits neurons to die before Bax function at the mitochondria, Bax-deficient neurons still become committed to die. 29 In striking contrast, Bax-deficient neurons exposed to ER stress fail to become committed to die (Figure 5b).…”