Mj. Courtney et Et. Coffey, The mechanism of Ara-C-induced apoptosis of differentiating cerebellar granule neurons, EUR J NEURO, 11(3), 1999, pp. 1073-1084
Neurotoxicity is one of the side-effects of the therapeutically useful anti
tumour agent, Ara-C (or 1-beta-D-arabinofuranosyl-cytosine, cytarabine). Th
is agent is also reported to induce cell death of cultured neurons. In this
study, we show that Ara-C-induced death of differentiating rat cerebellar
granule neurons is prevented by cycloheximide at concentrations correspondi
ng to its action in preventing protein synthesis. The death is accompanied
by cleavage of the caspase substrate poly ADP ribose polymerase (PARP) and
c-Abl-dependent activation of the stress-activated protein kinases c-Jun N-
terminal kinase and p38. However, c-Jun levels do not rise and the activati
on of the stress-activated protein kinases is not required for this form of
neuronal death. Cyclin-dependent kinase (cdk) activity and inappropriate c
ell-cycle re-entry have been implicated in some forms of death in different
iated neurons. Here we show that Ara-C-induced death of cerebellar granule
neurons is prevented by an inhibitor of cdk4, whereas inhibition of cdk1, -
2 and -5 mimics the death, and non-cdk4/6 cdks are inhibited by Ara-C treat
ment. Cdk1 and -2 are dramatically downregulated during neuronal differenti
ation, and neither Ara-C nor inhibition of these cdks induces death in matu
re neurons. This mechanism could also play a significant role in the neurot
oxicity associated with the therapeutic use of Ara-C, as cdk levels can be
upregulated in stressed neurons of adult brain. We propose that the balance
between cdk4/6 and cdk1/2/5 activity may determine the survival of early d
ifferentiating neurons, and that DNA-damaging agents may induce neuronal de
ath by inhibiting cdk1/2/5 under conditions which require these activities
for survival.