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Research ArticleArticle

Bryostatin 1 and UCN-01 Potentiate 1-β-d-Arabinofuranosylcytosine-Induced Apoptosis in Human Myeloid Leukemia Cells through Disparate Mechanisms

Shujie Wang, Zhiliang Wang and Steven Grant
Molecular Pharmacology January 2003, 63 (1) 232-242; DOI: https://doi.org/10.1124/mol.63.1.232
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Abstract

The effects of the PKC activator and down-regulator bryostatin 1 and the PKC and Chk1 inhibitor 7-hydroxystaurosporine (UCN-01) were compared with respect to potentiation of 1-β-d-arabinofuranosylcytosine (ara-C)-induced apoptosis in human myelomonocytic leukemia cells (U937). Whereas bryostatin 1 and UCN-01 both markedly enhanced ara-C–induced mitochondrial injury (e.g., cytochrome c and Smac/DIABLO release, loss of mitochondrial membrane potential), caspase activation, and apoptosis, ectopic expression of an N-terminal loop-deleted Bcl-2 mutant protein protected cells from ara-C/UCN-01– but not ara-C/bryostatin 1-mediated lethality. Conversely, ectopic expression of CrmA or dominant-negative caspase-8 abrogated potentiation of ara-C–mediated apoptosis by bryostatin 1 but not by UCN-01. Exposure of cells to ara-C and bryostatin 1 (but not UCN-01) resulted in sustained release of tumor necrosis factor (TNF) α; moreover, potentiation of ara-C lethality by bryostatin 1 (but not by UCN-01) was reversed by coadministration of TNF soluble receptors or the selective PKC inhibitor bisindolylmaleimide (1 μM). Finally, similar events were observed in the human promyelocytic leukemia cell line HL-60. Together, these findings suggest that potentiation of ara-C lethality in human myeloid leukemia cells by bryostatin 1 but not UCN-01 involves activation of the extrinsic, receptor-mediated apoptotic pathway, and represents a consequence of bryostatin 1-mediated release of TNF-α. They also argue that the mechanism by which bryostatin 1 promotes ara-C–induced mitochondrial injury, caspase activation, and apoptosis involves factors other than or in addition to PKC down-regulation or modulation of Bcl-2 phosphorylation status.

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Molecular Pharmacology: 63 (1)
Molecular Pharmacology
Vol. 63, Issue 1
1 Jan 2003
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Research ArticleArticle

Bryostatin 1 and UCN-01 Potentiate 1-β-d-Arabinofuranosylcytosine-Induced Apoptosis in Human Myeloid Leukemia Cells through Disparate Mechanisms

Shujie Wang, Zhiliang Wang and Steven Grant
Molecular Pharmacology January 1, 2003, 63 (1) 232-242; DOI: https://doi.org/10.1124/mol.63.1.232

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Research ArticleArticle

Bryostatin 1 and UCN-01 Potentiate 1-β-d-Arabinofuranosylcytosine-Induced Apoptosis in Human Myeloid Leukemia Cells through Disparate Mechanisms

Shujie Wang, Zhiliang Wang and Steven Grant
Molecular Pharmacology January 1, 2003, 63 (1) 232-242; DOI: https://doi.org/10.1124/mol.63.1.232
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