BCR-ABL Delays Apoptosis Upstream of Procaspase-3 Activation

Dubrez, Laurence; Eymin, Béatrice; Sordet, Olivier; Droin, Nathalie; Turhan, Ali G; Solary, Éric

doi:10.1182/blood.v91.7.2415.2415_2415_2422

Cited by 26 publications

(30 citation statements)

References 31 publications

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“…It has been reported that Bcr-Abl delays apoptosis by blocking cytochrome c release and caspase 3 activation. 30) Ceparanthine at 5-10 µM caused remarkable degradation of the Bcr-Abl protein and induced apoptosis in K562 cells. 31) Inhibition of tyrosine kinase activity of Bcr-Abl by STI571 also induced apoptosis.…”

Section: Discussionmentioning

confidence: 98%

Reversal of the resistance to STI571 in human chronic myelogenous leukemia K562 cells

Mukai

Fang²,

Furukawa³

et al. 2003

Cancer Science

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STI571, an Abl-specific tyrosine kinase inhibitor, selectively kills Bcr-Abl-containing cells in vitro and in vivo. However, some chronic myelogenous leukemia (CML) cell lines are resistant to STI571. We evaluated whether STI571 interacts with P-glycoprotein (P-gp) and multidrug resistance protein 1 (MRP1), and examined the effect of agents that reverse multidrug resistance (MDR) on the resistance to SI571 in MDR cells. STI571 inhibited the [ 125 I]azidoagosterol A-photolabeling of P-gp, but not that of MRP1. K562/MDR cells that overexpress P-gp were 3.67 times more resistant to STI571 than the parental Philadelphia-chromosome-positive (Ph + + + +) CML K562 cells, and this resistance was most effectively reversed by cepharanthine among the tested reversing agents. The concentration of STI571 required to completely inhibit tyrosine phosphorylation in K562/MDR cells was about 3 times higher than that in K562 cells, and cepharanthine abolished the difference. In KB-G2 cells that overexpress P-gp, but not BcrAbl, 2.5 µ µ µ µM STI571 partly reversed the resistance to vincristine (VCR), paclitaxel, etoposide (VP-16) and actinomycin D (ACD) but not to Adriamycin (ADM) or colchicine. STI571 increased the accumulation of VCR, but not that of ADM in KB-G2 cells. STI571 did not reverse resistance to any agent in KB/MRP cells that overexpress MRP1. These findings suggest that STI571 is a substrate for P-gp, but is less efficiently transported by P-gp than VCR, and STI571 is not a substrate for MRP1. Among the tested reversing agents that interact with P-gp, cepharanthine was the most effective agent for the reversal of the resistance to STI571 in K562/ MDR cells. Furthermore, STI571 itself was a potent reversing agent for MDR in P-gp-expressing KB-G2 cells. (Cancer Sci 2003; 94: 557-563)

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Section: Discussionmentioning

confidence: 98%

Reversal of the resistance to STI571 in human chronic myelogenous leukemia K562 cells

Mukai

Fang²,

Furukawa³

et al. 2003

Cancer Science

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“…Mice transgenic for a p190 bcr/abl construct controlled by the ubiquitously expressed promoter, metallothionein, have constitutive activation of ABL protein kinase and develop pre-B leukemias and lymphomas after a latent period of 7 weeks or more (76)(77)(78)(79). In progenitor B-cell lines, ABL deficiency increases sensitivity to apoptosis, while p190 bcr/abl inhibits apoptosis (80)(81)(82)(83). While c-ABL has also been implicated in regulating cell cycle and cell growth, these in vitro apoptotic findings have raised the possibility that ABL may exert its effects by modulating apoptotic activity of B-lineage cells in vivo.…”

Section: C-abl Protooncogene-modified Mice: Abl Protein Tyrosine Kinamentioning

confidence: 99%

“…p53 deletion is associated with increased Bcl-2 and decreased Bax protein levels in non-myeloid tissues (106), making it probable that p53 modulates apoptosis among pro-B cells by a similar mechanism. In cell lines, overexpression of ABL inhibits apoptosis by inducing anti-apoptotic proteins of the Bcl-2 family (82). Other than involvement of Bcl-2 family proteins, however, the triggering and signaling pathways operating at the early B-cell checkpoint remain obscure, and a subject for future work.…”

Section: Apoptotic Modulation Of B-cell Genesismentioning

confidence: 99%

Apoptosis and its modulation during B lymphopoiesis in mouse bone marrow

Lü

Osmond

2000

Immunological Reviews

105

127

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Studies in normal, gene-deleted, transgenic and mutant mice have examined apoptotic cell death and its role in B lymphopoiesis in bone marrow. Apoptotic activity has been quantitated among phenotypically defined populations of precursor B cells using flow cytometry of apoptotic cells and an established model of B-cell development. In normal mice, the frequencies of apoptotic cells (apoptotic index) and accumulation of apoptotic cells during short-term culture (apoptotic rate) are maximal at around the pro/pre-B-cell transition and among immature B lymphocytes. The brief period between onset of apoptosis and clearance by macrophages (apoptotic transit time) is similar for most precursor B-cells. Apoptosis-modulating factors produce substantial changes in apoptotic activity among pro-B and pre-B cells, associated with altered expression of bcl-2 family proteins. Pro-B-cell apoptosis, normally extensive, is markedly suppressed in the absence of p53. Complete pro-B-cell abortion in RAG-2 deletion provides an assay for apoptotic fractions in other experimental systems. Pre-B-cell apoptosis is enhanced by deficiencies of interleukin (IL)-7, Abl protooncogene or colony-stimulating factor (CSF)-1 and overexpression of heat-stable antigen, and is inhibited by IL-7 and p190bcr/abl transgenes. CSF-1 and melatonin administration inhibit pre-B-cell apoptosis, probably via stromal cell stimulation. Such apoptotic modulation has implications for B-cell homeostasis, quality control, immunodeficiency and neoplasia.

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“…Among other molecules that can interfere with this cell death pathway (13,14) is the small heat shock protein HSP27. Small heat shock proteins are overexpressed in response to environmental stresses (15); they vary in size from 15 to 30 kDa and share sequence homologies and biochemical properties such as phosphorylation and oligomerization (16).…”

mentioning

confidence: 99%

HSP27 inhibits cytochrome c‐dependent activation of procaspase‐9

et al. 1999

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We have previously shown that the small heat shock protein HSP27 inhibited apoptotic pathways triggered by a variety of stimuli in mammalian cells. The present study demonstrates that HSP27 overexpression decreases U937 human leukemic cell sensitivity to etoposide-induced cytotoxicity by preventing apoptosis. As observed for Bcl-2, HSP27 overexpression delays poly(ADP-ribose)polymerase cleavage and procaspase-3 activation. In contrast with Bcl-2, HSP27 overexpression does not prevent etoposide-induced cytochrome c release from the mitochondria. In a cell-free system, addition of cytochrome c and dATP to cytosolic extracts from untreated cells induces the proteolytic activation of procaspase-3 in both control and bcl-2-transfected U937 cells but fails to activate procaspase-3 in HSP27-overexpressing cells. Immunodepletion of HSP27 from cytosolic extracts increases cytochrome c/dATP-mediated activation of procaspase-3. Overexpression of HSP27 also prevents procaspase-9 activation. In the cell-free system, immunodepletion of HSP27 increases LEDH-AFC peptide cleavage activity triggered by cytochrome c/dATP treatment. We conclude that HSP27 inhibits etoposide-induced apoptosis by preventing cytochrome c and dATP-triggered activity of caspase-9, downstream of cytochrome c release.

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BCR-ABL Delays Apoptosis Upstream of Procaspase-3 Activation

Cited by 26 publications

References 31 publications

Reversal of the resistance to STI571 in human chronic myelogenous leukemia K562 cells

Reversal of the resistance to STI571 in human chronic myelogenous leukemia K562 cells

Apoptosis and its modulation during B lymphopoiesis in mouse bone marrow

HSP27 inhibits cytochrome c‐dependent activation of procaspase‐9

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