Synergistic Induction of Apoptosis in Human Myeloid Leukemia Cells by Phorbol 12-Myristate 13-Acetate and Flavopiridol Proceeds via Activation of Both the Intrinsic and Tumor Necrosis Factor-Mediated Extrinsic Cell Death Pathways

Abstract Previous studies have shown that certain low molecular weight polar solvents downregulate c-myc gene expression and induce terminal differentiation of human HL-60 myeloid leukemia cells. We have examined the effects of ethanol on gene expression in this cell line. The results show that while ethanol induces a more differentiated phenotype, this agent has little effect on the self-renewal capacity of HL-60 cells. Ethanol treatment was also associated with a concentration- dependent and transient downregulation of c-myc transcripts. Similar effects were observed for c-myb mRNA levels. The results further show that ethanol exposure is associated with induction of tumor necrosis factor gene expression. These findings indicate that ethanol induces changes in specific gene expression during non-terminal differentiation of HL-60 cells. The clinical effects of this agent could thus be related to altered patterns of gene expression in hematopoietic or other cells.

Download Full-text

Differential biologic effects resulting from bimodal binding of recombinant human tumor necrosis factor to myeloid leukemia cells

Blood ◽

10.1182/blood.v73.2.419.419 ◽

1989 ◽

Vol 73 (2) ◽

pp. 419-424 ◽

Cited By ~ 18

Author(s):

H Ishikura ◽

K Hori ◽

A Bloch

Keyword(s):

Tumor Necrosis Factor ◽

Myeloid Leukemia ◽

Tumor Necrosis ◽

Human Tumor ◽

Leukemia Cells ◽

Affinity Binding ◽

Dependent Manner ◽

High Affinity Binding ◽

High Affinity ◽

Necrosis Factor

Abstract Human recombinant tumor necrosis factor (rTNF) bound to ML-1 and HL-60 human myeloid leukemia cells in a bimodal manner. Saturable high- affinity binding was maximal at approximately 3 nmol/L rTNF, whereas saturable low-affinity binding reached its maximum at approximately 30 nmol/L. As analyzed by computer program, the observed data fit a two- receptor site model, with p less than .05. High-affinity binding concentrations of rTNF caused the differentiation of both cell lines, whereas low-affinity binding concentrations abolished this effect in a concentration-dependent manner. Thus, the type of biologic response elicited with rTNF in these cells is a function of the concentration at which the factor is applied. If generally applicable, this bimodal effect may require consideration when rTNF is to be used therapeutically.

Download Full-text

The Histone Deacetylase Inhibitor Sodium Butyrate Interacts Synergistically with Phorbol Myristate Acetate (PMA) to Induce Mitochondrial Damage and Apoptosis in Human Myeloid Leukemia Cells through a Tumor Necrosis Factor-α-Mediated Process

Experimental Cell Research ◽

10.1006/excr.2002.5548 ◽

2002 ◽

Vol 277 (1) ◽

pp. 31-47 ◽

Cited By ~ 34

Author(s):

Mohamed Rahmani ◽

Yun Dai ◽

Steven Grant

Keyword(s):

Tumor Necrosis Factor ◽

Histone Deacetylase Inhibitor ◽

Myeloid Leukemia ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Leukemia Cells ◽

Myristate Acetate ◽

Deacetylase Inhibitor ◽

Factor Α ◽

Necrosis Factor

Download Full-text

NFκB Controls the Balance between Fas and Tumor Necrosis Factor Cell Death Pathways during T Cell Receptor-induced Apoptosis Via the Expression of Its Target Gene A20

Journal of Biological Chemistry ◽

10.1074/jbc.m304000200 ◽

2003 ◽

Vol 278 (35) ◽

pp. 32825-32833 ◽

Cited By ~ 29

Author(s):

Michal Malewicz ◽

Nicolas Zeller ◽

Z. Buket Yilmaz ◽

Falk Weih

Keyword(s):

Cell Death ◽

T Cell ◽

Tumor Necrosis Factor ◽

T Cell Receptor ◽

Tumor Necrosis ◽

Target Gene ◽

Cell Receptor ◽

Cell Death Pathways ◽

Induced Apoptosis ◽

Necrosis Factor

Download Full-text

Differential biologic effects resulting from bimodal binding of recombinant human tumor necrosis factor to myeloid leukemia cells

Blood ◽

10.1182/blood.v73.2.419.bloodjournal732419 ◽

1989 ◽

Vol 73 (2) ◽

pp. 419-424

Author(s):

H Ishikura ◽

K Hori ◽

A Bloch

Keyword(s):

Tumor Necrosis Factor ◽

Myeloid Leukemia ◽

Tumor Necrosis ◽

Human Tumor ◽

Leukemia Cells ◽

Affinity Binding ◽

Dependent Manner ◽

High Affinity Binding ◽

High Affinity ◽

Necrosis Factor

Human recombinant tumor necrosis factor (rTNF) bound to ML-1 and HL-60 human myeloid leukemia cells in a bimodal manner. Saturable high- affinity binding was maximal at approximately 3 nmol/L rTNF, whereas saturable low-affinity binding reached its maximum at approximately 30 nmol/L. As analyzed by computer program, the observed data fit a two- receptor site model, with p less than .05. High-affinity binding concentrations of rTNF caused the differentiation of both cell lines, whereas low-affinity binding concentrations abolished this effect in a concentration-dependent manner. Thus, the type of biologic response elicited with rTNF in these cells is a function of the concentration at which the factor is applied. If generally applicable, this bimodal effect may require consideration when rTNF is to be used therapeutically.

Download Full-text

Induction of tumor necrosis factor by bryostatin 1 is involved in synergistic interactions with paclitaxel in human myeloid leukemia cells

Blood ◽

10.1182/blood-2002-09-2739 ◽

2003 ◽

Vol 101 (9) ◽

pp. 3648-3657 ◽

Cited By ~ 13

Author(s):

Shujie Wang ◽

Zhiliang Wang ◽

Paul Dent ◽

Steven Grant

Keyword(s):

Tumor Necrosis Factor ◽

Myeloid Leukemia ◽

Tumor Necrosis ◽

Ectopic Expression ◽

Leukemia Cells ◽

Wild Type ◽

Bryostatin 1 ◽

Mitochondrial Injury ◽

Tnf Α ◽

Necrosis Factor

Interactions between the protein kinase C (PKC) activator/down-regulator bryostatin 1 and paclitaxel have been examined in human myeloid leukemia cells (U937) and in highly paclitaxel-resistant cells ectopically expressing a Bcl-2 phosphorylation loop–deleted protein (ΔBcl-2). Treatment (24 hours) of wild-type cells with paclitaxel (eg, 5 to 20 nM) in combination with 10 nM bryostatin 1 induced a marked increase in mitochondrial damage (eg, cytochrome c and Smac/DIABLO [second mitochondria-derived activator of caspases/direct IAP binding protein with low pI] release), caspase activation, Bid cleavage, and apoptosis; moreover, bryostatin 1 circumvented the block to paclitaxel-induced mitochondrial injury and apoptosis conferred by ectopic expression of the loop-deleted protein. Coadministration of tumor necrosis factor (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 events occurred 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-α mRNA and protein and was mimicked by exogenous TNF-α. Coadministration of the selective PKC inhibitor GFX (1 μM) blocked the increase in TNF-α mRNA levels and apoptosis in bryostatin 1/paclitaxel–treated cells. Lastly, synchronization of cells in G2M increased their sensitivity to TNF-α–associated lethality. Collectively, these findings indicate that in U937 cells, bryostatin 1 promotes paclitaxel-mediated mitochondrial injury and apoptosis, and circumvents resistance to cell death conferred by loss of the Bcl-2 phosphorylation domain, through the PKC-dependent induction of TNF-α. They further suggest that this process is amplified by paclitaxel-mediated arrest of cells in G2M, where they are more susceptible to TNF-α–induced lethality.

Download Full-text