Chloroquine-induced neuronal cell death is p53 and Bcl-2 family-dependent but caspase-independent.
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.
Zaidi
A U
AU
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, 63110, USA.
McDonough
J S
JS
Klocke
B J
BJ
Latham
C B
CB
Korsmeyer
S J
SJ
Flavell
R A
RA
Schmidt
R E
RE
Roth
K A
KA
D000563:Amebicides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology*; D004622:Embryo, Mammalian; D005260:Female; D019254:Genes, bcl-2 / Q000502:physiology*; D016158:Genes, p53 / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D011247:Pregnancy; D013687:Telencephalon / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure
D000563:Amebicides; D002738:Chloroquine; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases