Expression of Apoptosis-Controlling Proteins in Acute Leukemia Cells

Campos, Lydia; Sabido, Odile; Viallet, Annie; Vasselon, C; Guyotat, Denis

doi:10.3109/10428199909058454

Cited by 51 publications

(31 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…There are several different mechanisms known to be involved in the development of MDR in human leukemia cell lines, including overexpression of the drug transporters Pglycoprotein (P-gp) or multidrug resistance-associated protein (MRP1), and alterations in apoptotic cell death mechanisms (Safa, 1998;Campos et al, 1993). We have found that PR3 expression is significantly decreased in the drug resistant HL-60 subline, HL-60/ ADR, compared to the sensitive HL-60 cells.…”

Section: Introductionmentioning

confidence: 57%

Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, is downregulated in its doxorubicin-resistant variant

Gordon

Rastegar

et al. 2002

Oncogene

View full text Add to dashboard Cite

We report here that expression of proteinase 3 (PR3), a serine protease, is down-regulated in the HL60/ADR multidrug resistant variant of the human myelogenous leukemia cell line HL-60, and that down-regulation of PR3 is associated with doxorubicin (DOX) resistance in these cells. To determine whether PR3 is involved in DOX-induced apoptosis in HL-60 cells, and whether its loss causes resistance to DOX, we inhibited PR3 expression by an anti-sense PR3 oligodeoxynucleotide and showed that inhibition of PR3 expression results in a significant reduction in DOX-induced DNA fragmentation and increased resistance to DOX-induced apoptosis. Our results revealed that PR3-mediated DOX-induced apoptosis in HL-60 cells is independent of the loss of mitochondrial membrane potential (DC m ) and activation of the caspase-8 and -9 pathways. Moreover, while PR3 is involved in the cleavage of caspase-3, PR3-mediated DOX-induced DNA fragmentation and apoptosis were not prevented by a specific inhibitor of caspase-3. These data suggest that activation of caspase-3 alone is not sufficient to trigger PR3-mediated DOX-induced apoptosis. Treatment with an anti-PR3 oligomer significantly decreased reactive oxygen species (ROS) generation in cells treated with low concentrations of DOX, revealing a role for PR3 in enhancing production of DOX-induced ROS. Moreover, DOX-induced apoptosis at 0.001 -0.01 mM was only inhibited in HL-60 cells pre-treated with the antioxidant N-acetyl-cysteine in the absence of anti-PR3, revealing that DOX-induced apoptosis in these cells is PR3-and ROS-dependent. Our results show that PR3 is involved in DOX-induced ROS-dependent apoptosis and that its loss is associated with resistance to DOX in HL-60 cells.

show abstract

Section: Introductionmentioning

confidence: 57%

Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, is downregulated in its doxorubicin-resistant variant

Gordon

Rastegar

et al. 2002

Oncogene

View full text Add to dashboard Cite

show abstract

“…While one study showed that high levels of procaspase 2 and 3 portended a poor survival in adult AML, other studies have found no relationship between the absolute levels of these proteins and outcome in both lymphoid and non-lymphoid disease. [32][33][34] Again, these discordant results may be related to the fact that baseline protein expression might not be reflective of enzyme activity that is induced upon exposure of leukemic cells to therapy. Estrov et al 32 found that the levels of cleaved (and presumably active) caspase-3 correlated with a favorable outcome in AML.…”

Section: Introductionmentioning

confidence: 99%

Diversity of the apoptotic response to chemotherapy in childhood leukemia

et al. 2002

View full text Add to dashboard Cite

Apoptosis is the primary mechanism through which most chemotherapeutic agents induce tumor cell death. The purpose of this study was to determine the extent to which blasts from children with leukemia undergo a uniform apoptotic death pathway in vivo. The expression of pro-and anti-apoptotic proteins p53, p21, MDM-2, BCL-2, BCL-X L , BCL-X S , and BAX, and caspase-3 activity was determined in circulating blasts collected from the peripheral blood of children with leukemia prior to, and at serial time points following chemotherapy. Culturing blasts ex vivo for 12 h assessed spontaneous apoptosis and the increment induced by chemotherapy. Baseline apoptosis varied between 3% and 29%. Twenty-four hours following chemotherapy the increase in the percentage of cells undergoing apoptosis ranged from Ͻ1% to 38%. Eleven of 20 patients who received initial treatment with a p53-dependent drug showed an increase in p53 expression. In these patients, the levels of p53 target genes were also increased. A uniform pattern of BCL-2 family protein expression was not observed and only a minority of samples showed a change that would favor apoptosis. We conclude that that the initial apoptotic response to chemotherapy in children with leukemia is variable involving both p53-dependent and p53-independent pathways.

show abstract

“…These proteins are potent inhibitors of cell death, and high expression levels are observed in many cancers (Adams and Cory, 1998;Reed, 1999). Bcl-2 itself is highly expressed in the majority of cases of acute leukaemia, approximately 50% of diffuse large B-cell lymphomas and up to 90% of malignant melanomas (Banker et al, 1997;Jansen et al, 1998;Campos et al, 1999;Skinnider et al, 1999). Forced expression of Bcl-2 results in resistance to a variety of proapoptotic stimuli, including growth factor withdrawal, cytotoxic chemotherapy and radiation, and there is some evidence that Bcl-2 also promotes resistance to anticancer immune responses.…”

mentioning

confidence: 99%

Small-molecule Bcl-2 inhibitors sensitise tumour cells to immune-mediated destruction

et al. 2007

View full text Add to dashboard Cite

The cytotoxic effects of anticancer immune cells are mediated by perforin/granzyme-B, Fas ligand and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), and therefore depend on intact apoptotic responses in target tumour cells. As killing by all three of these mechanisms is blocked by the frequently overexpressed antiapoptotic oncoprotein Bcl-2, we hypothesised that coexposure to a Bcl-2 inhibitor might enhance anticancer immune responses. We evaluated this in U937 lymphoma cells, and A02 melanoma cells, which both show strong Bcl-2 expression. Va24 þ Vb11 þ natural killer T (NKT) cells expanded from peripheral blood of normal donors (n ¼ 3) were coincubated with PKH26-labelled U937 cells, and cytotoxicity was determined by flow cytometry after annexin-V-FITC and 7-AAD staining. In all cases, addition of the HA14-1 small-molecule Bcl-2 inhibitor to the cocultures significantly increased apoptosis in the target U937 cells. Using a similar assay, killing of A02 cells by the cytotoxic T-lymphocyte clone 1H3 was shown to be amplified by coexposure to the potent small-molecule Bcl-2 inhibitor ABT-737. Experiments with immune effectors preincubated with concanamycin-A suggested that sensitisation to perforin/granzyme-B may underlie enhanced target-cell killing observed in the presence of Bcl-2 inhibitors. We conclude that immune destruction of malignant cells can be amplified by molecular interventions that overcome Bcl-2-mediated resistance to apoptosis.

show abstract

Expression of Apoptosis-Controlling Proteins in Acute Leukemia Cells

Cited by 51 publications

References 25 publications

Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, is downregulated in its doxorubicin-resistant variant

Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, is downregulated in its doxorubicin-resistant variant

Diversity of the apoptotic response to chemotherapy in childhood leukemia

Small-molecule Bcl-2 inhibitors sensitise tumour cells to immune-mediated destruction

Contact Info

Product

Resources

About