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Vol. 301, Issue 2, 568-577, May 2002

Bryostatin 1 Increases 1-beta -D-Arabinofuranosylcytosine-Induced Cytochrome c Release and Apoptosis in Human Leukemia Cells Ectopically Expressing Bcl-xL

Zhiliang Wang, Shujie Wang, Yun Dai and Steven Grant

Departments of Medicine (Z.W., S.G.), Biochemistry (S.W., S.G.), and Pharmacology (S.G.), Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia

The ability of the protein kinase C down-regulator bryostatin 1 to potentiate 1-beta -D-arabinofuranosylcytosine (ara-C)-induced apoptosis was examined in human leukemia cells (U937) over-expressing the antiapoptotic protein Bcl-xL. Coadministration of bryostatin 1 with ara-C resulted in enhanced cytosolic release of cytochrome c and Smac/DIABLO, procaspase-3 and -9 activation, loss of mitochondrial membrane potential (Delta psi m), poly(ADP-ribosyl)phosphorylase degradation, apoptosis, and loss of clonogenic survival in U937/Bcl-xL cells, although effects were not as marked as in empty-vector control cells. Whereas the broad caspase inhibitor ZVAD-fluoromethyl ketone blocked ara-C/bryostatin 1-mediated caspase activation, loss of Delta psi m, and apoptosis in U937 cells, it failed to diminish cytochrome c release. In contrast, ectopic expression of Bcl-xL blocked cytochrome c redistribution as well as all other events involved in ara-C/bryostatin 1-mediated apoptosis. The ability of ectopic expression of cytokine response modifier A to attenuate, albeit partially, bryostatin 1-mediated potentiation of ara-C-related apoptosis suggested a contributory role for activation of the extrinsic pathway in this phenomenon. Finally, the F0F1 ATPase inhibitor oligomycin effectively blocked cytochrome c release as well as loss of Delta psi m and apoptosis in U937/Bcl-xL cells. Together, these findings support the concept that bryostatin 1 potentiates ara-C lethality in human leukemia cells ectopically expressing Bcl-xL by diminishing the capacity of this antiapoptotic protein to antagonize cytochrome c release. In addition, they raise the possibility that activation of caspase cascades operating independently of Bcl-xL-associated mitochondrial actions may also contribute to enhanced lethality.

0022-3565/02/3012-0568$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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