Journal
LEUKEMIA
Volume 15, Issue 9, Pages 1388-1397Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.leu.2402201
Keywords
apoptosis; B-CLL; apoptosome; proteasome inhibitors; caspases
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Proteasome inhibitors, including lactacystin and MG132 (carbobenzoxyl-leucinyl-leucinyl-leucinal), potently induce apoptosis in leukaemic B cells from patients with B cell chronic lymphocytic leukaemia (B-CLL). This pro-apoptotic effect occurs in cells from patients at all stages of the disease, including those resistant to conventional chemotherapy, suggesting that proteasome inhibitors may be useful for treatment of B-CLL. Following initial inhibition of proteasomal activity, these agents induce mitochondrial cytochrome c release and caspase-dependent apoptosis, involving cleavage/activation of caspases -2, -3, -7, -8 and -9. Pre-treatment with the cell permeable caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe)fluoromethyl ketone (Z-VAD.fmk), did not prevent the release of cytochrome c or partial processing of caspase-9 but prevented activation of effector caspases and the induction of apoptosis. These results suggest that the release of cytochrome c is caspase independent and that caspase-9 is the initiator caspase in proteasome inhibitor-induced apoptosis of ll cells. Activation of B-CLL lysates with dATP results in the formation of an similar to 700 kDa caspase-activating apoptosome complex containing Ail We describe for the first time the formation of a similar similar to 700 kDa caspase-activating apoptosome complex in B-Cli cells induced to undergo apoptosis by proteasome inhibitors.
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