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. 2001 Oct;60(10):937-45.
doi: 10.1093/jnen/60.10.937.

Chloroquine-induced neuronal cell death is p53 and Bcl-2 family-dependent but caspase-independent

A U Zaidi  1 , J S McDonough, B J Klocke, C B Latham, S J Korsmeyer, R A Flavell, R E Schmidt, K A Roth
Affiliations

Chloroquine-induced neuronal cell death is p53 and Bcl-2 family-dependent but caspase-independent

A U Zaidi et al. J Neuropathol Exp Neurol. 2001 Oct.

Abstract

Chloroquine is a lysosomotropic agent that causes marked changes in intracellular protein processing and trafficking and extensive autophagic vacuole formation. Chloroquine may be cytotoxic and has been used as a model of lysosomal-dependent cell death. Recent studies indicate that autophagic cell death may involve Bcl-2 family members and share some features with caspase-dependent apoptotic death. To determine the molecular pathway of chloroquine-induced neuronal cell death, we examined the effects of chloroquine on primary telencephalic neuronal cultures derived from mice with targeted gene disruptions in p53, and various caspase and bcl-2 family members. In wild-type neurons, chloroquine produced concentration- and time-dependent accumulation of autophagosomes, caspase-3 activation, and cell death. Cell death was inhibited by 3-methyladenine, an inhibitor of autophagic vacuole formation, but not by Boc-Asp-FMK (BAF), a broad caspase inhibitor. Targeted gene disruptions of p53 and bax inhibited and bcl-x potentiated chloroquine-induced neuron death. Caspase-9- and caspase-3-deficient neurons were not protected from chloroquine cytotoxicity. These studies indicate that chloroquine activates a regulated cell death pathway that partially overlaps with the apoptotic cascade.

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