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Prepublished online as a Blood First Edition Paper on January 9, 2003; DOI 10.1182/blood-2002-09-2739. This Article Full Text (PDF) All Versions of this Article: 2002-09-2739v1 101/9/3648    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wang, S. Articles by Grant, S. Search for Related Content PubMed PubMed Citation Articles by Wang, S. Articles by Grant, S. Social Bookmarking                   What's this? Submitted September 16, 2002 Accepted December 15, 2002 Induction of tumor necrosis factor by bryostatin 1 is involved in synergistic interactions with paclitaxel in human myeloid leukemia cells Shujie Wang, Zhiliang Wang, Paul Dent, and Steven Grant* Department of Biochemistry, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA, USA Division of Hematology/Oncology, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA, USA Department of Radiation Oncology, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA, USA * Corresponding author; email: stgrant{at}hsc.vcu.edu. Interactions between the protein kinase C (PKC) activator and down-regulator bryostatin 1 and paclitaxel have been examined in human myeloid leukemia cells (U937) as well as in highly paclitaxel-resistant cells ectopically expressing a Bcl-2 phosphorylation loop-deleted protein (Bcl-2). Combined treatment (24 h) of wild-type cells with paclitaxel (e.g., 5-20 nM) in combination with 10 nM bryostatin 1 resulted in a marked increase in mitochondrial damage (e.g., cytochrome c and Smac/DIABLO release), caspase activation, Bid cleavage, and apoptosis; moreover, administration of bryostatin 1 circumvented the block to paclitaxel-induced mitochondrial injury and apoptosis conferred by ectopic expression of the loop-deleted protein. Co-administration of TNF soluble receptors, or ectopic expression of CrmA or dominant-negative caspase-8, abrogated potentiation of paclitaxel-induced mitochondrial injury and apoptosis by bryostatin 1, implicating the extrinsic apoptotic pathway in this process. Similar findings were noted in HL-60 leukemia cells. Potentiation of paclitaxel-induced apoptosis in wild-type and mutant cells by bryostatin 1 was associated with increases in TNF mRNA and protein, and was mimicked by exogenous TNF. Co-administration of the selective PKC inhibitor GFX (1 µM) blocked the increase in TNF mRNA levels and apoptosis in bryostatin 1/paclitaxel-treated cells. Lastly, synchronization of cells in G2M increased their sensitivity to TNF-associated lethality. Collectively, these findings indicate that in U937 cells, bryostatin 1 promotes paclitaxel-mediated mitochondrial injury and apoptosis, and circumvents the block to cell death conferred by loss of the Bcl-2 phosphorylation domain, through the PKC-dependent induction of TNF. They further suggest that this process is amplified by paclitaxel-mediated arrest of cells in G2M, where they are more susceptible to TNF-induced lethality. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: W.-C. Chou, C. Jie, A. A. Kenedy, R. J. Jones, M. A. Trush, and C. V. Dang Role of NADPH oxidase in arsenic-induced reactive oxygen species formation and cytotoxicity in myeloid leukemia cells PNAS, March 30, 2004; 101(13): 4578 - 4583. [Abstract] [Full Text] [PDF]

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