Paclitaxel targets mitochondria upstream of caspase activation in intact human neuroblastoma cells.
We previously reported that paclitaxel acted directly on mitochondria isolated from human neuroblastoma SK-N-SH cells. Here, we demonstrate that the direct mitochondrial effect of paclitaxel observed in vitro is relevant in intact SK-N-SH cells. After a 2 h incubation with 1 microM paclitaxel, the mitochondria were less condensed. Paclitaxel (1 microM, 1-4 h) also induced a 20% increase in respiration rate and a caspase-independent production of reactive oxygen species by mitochondria. The paclitaxel-induced release of cytochrome c was detected only after 24 h of incubation, was caspase-independent and permeability transition pore-dependent. Thus, paclitaxel targets mitochondria upstream of caspase activation, early during the apoptotic process in intact human neuroblastoma cells.
André
Nicolas
N
UMR 6032, University of la Méditerranée, UFR of Pharmacy, 27 Bd Jean Moulin, 13005 Marseille, France.
Carré
Manon
M
Brasseur
Gaël
G
Pourroy
Bertrand
B
Kovacic
Hervé
H
Briand
Claudette
C
Braguer
Diane
D
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects; D003574:Cytochrome c Group / Q000378:metabolism; D016503:Drug Delivery Systems; D004789:Enzyme Activation; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000648:ultrastructure; D017239:Paclitaxel / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D003574:Cytochrome c Group; D017382:Reactive Oxygen Species; D020169:Caspases; D017239:Paclitaxel