Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The apoptosis failure in cytostatic treatment of haemoblastosis is one of the means of chemoresistance. We were interested in the relationship of the after-doxorubicin-treatment-AML cells apoptosis and the immunophenotype, selected clinical and laboratory parameters, and also the P-gp, MRP, LRP, Bcl-2, Bax proteins expression. All analysis were evaluated with the flow cytometry method. To detect apoptotic cells in the sample, we used three methods: annexin test, TUNEL (TdT-mediated dUTP nick end labeling) test, and caspase 8 detection. After the cell cultivation the statisticaly important increase of apoptotic cells in the culture was apparent. The relation between the AML blast in vitro reaction and some clinical parameters such as the age of patient, white blood cell count, and blast percentage was also observed.
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PMID:The multidrug resistance and apoptosis evaluation in acute myeloid leukemia cells after the in vitro doxorubicin treatment. 1556 36

Product of Bcl-2 gene prolongs survival of hematopoietic cells by inhibition of programmed cell death. The aim of this study is to examine the expression of the bcl-2 protein in a group of patients with AML and its relation to clinical features and response to therapy. Slides from the bone marrow or peripheral blood of 70 patients with AML were assessed for the expression of bcl-2 by immunocytochemistry. The expression of myeloid and non-lineage associated markers was detected by indirect immunofluorescence method. Correlation between bcl-2 and markers expression and patients characteristics was determined. More than 20% positivity for bcl-2 was found in 22 (31.4%) patients. Bcl-2 expression showed an association with M4 and M5 subtypes (p<0.01) and was correlated with clinical parameters including WBC and platelet count, extramedullary disease and Hb level. Bcl-2 expressing cells were significantly higher in CD15(+) and CD13(+) patients and lower in CD11b(+) and CD33(+) cases (p<0.001). Complete remission (CR) rate was significantly lower in cases with 20% or more bcl-2 positivity than others (24.4% v 75.6%). A shorter CR duration was observed in bcl-2+ patients when compared with bcl-2- ones (571+/-50 versus 850+/-17 days)(p=0.0001). The expression of bcl-2 was also associated with shorter survival (p=0.0001). Survival time for bcl-2+ patients was 831+/-44 days versus 1119+/-17 days for bcl-2- ones. CD11b and CD33 positivity was associated with longer survival whereas CD13 and CD15 positivity was correlated with lower survival (p<0.007). In multivariate analysis bcl-2 positivity was associated with poor survival. Bcl-2 expression showed a prognostic value in our patients indicating that even despite of some differences in treatment regimen, immunocytochemical analysis of this marker is still a simple and inexpensive method for evaluation of prognosis in AML patients. Bcl-2 expression may be related to the expression of differentiation associated markers.
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PMID:Bcl-2 expression in acute myelogenous leukemia: the relation to myeloid antigen expression and response to therapy in Iranian patients. 1580 Jul 8

The MEK/MAPK signaling module is a key integration point along signal transduction cascades that regulate cell growth, survival, and differentiation, and is aberrantly activated in many human tumors. In tumor cells, constitutive MAPK activation affords increased proliferation and resistance to apoptotic stimuli, including classical cytotoxic drugs. In most instances, however, MAPK inhibition has cytostatic rather than cytotoxic effects, which may explain the lack of objective responses observed in early clinical trials of MEK inhibitors. Nevertheless, amenability of the MAPK pathway to pharmacodynamic evaluation and negligible clinical toxicity make MEK inhibitors an ideal platform to build pharmacological combinations with synergistic antitumor activity. In AML, the MEK/MAPK pathway is constitutively activated in the majority of cases (75%), conferring a uniformly poor prognosis; in preclinical models of AML, MEK blockade profoundly inhibits cell growth and proliferation and downregulates the expression of several anti-apoptotic players, thereby lowering the apoptotic threshold. Apoptosis induction, however, requires concentrations of MEK inhibitors much higher than those required to inhibit proliferation. Nevertheless, MEK blockade efficiently and selectively sensitizes leukemic cells to sub-optimal doses of other apoptotic stimuli, including classical cytotoxics (nucleoside analogs, microtubule-targeted drugs, gamma-irradiation), biologicals (retinoids, interferons, arsenic trioxide), and, most interestingly, other signal transduction/apoptosis modulators (UCN-01, STI571, Bcl-2 antagonists). In most instances, these MEK inhibition-based combinations result in a striking pro-apoptotic synergism in preclinical models. Here we briefly discuss evidence suggesting that MAPK pathway inhibition could play a prominent role in the development of integrated therapeutic strategies aimed at synergistic anti-leukemic effects.
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PMID:Beyond single pathway inhibition: MEK inhibitors as a platform for the development of pharmacological combinations with synergistic anti-leukemic effects. 1610 55

Interactions between the cyclin-dependent kinase (CDK) inhibitor flavopiridol and histone deacetylase (HDAC) inhibitors (suberoylanilide hydroxamide and sodium butyrate) were examined in human leukemia cells (U937 and HL-60) ectopically expressing Bcl-2/Bcl-x(L) and in primary AML cells. Coadministration of flavopiridol with HDAC inhibitors synergistically potentiated mitochondrial damage (cytochrome c, second mitochondria-derived activator of caspases/direct IAP binding protein with low pI, and apoptosis-inducing factor release), caspase activation, poly(ADP-ribose) polymerase degradation, and cell death in both wild type and Bcl-2- or Bcl-x(L)-overexpressing cells and induced a pronounced loss of clonogenicity. In contrast, Bcl-2 and Bcl-x(L) largely blocked these events in cells exposed to the cytotoxic agent 1-beta-d-arabinofuranosylcytosine (ara-C). Enforced expression of dominant-negative Fas-associated death domain failed to protect cells from the flavopiridol/histone deacetylase inhibitor (HDACI) regimen, arguing against the involvement of the receptor pathway in lethality. Ectopic expression of a phosphorylation loop-deleted Bcl-2 or Bcl-2 lacking the serine(70) phosphorylation site, which dramatically protected cells from ara-C lethality, delayed but did not prevent flavopiridol/HDAC inhibitor-induced mitochondrial injury, cell death, or loss of clonogenicity. Ectopic expression of Bcl-2 or Bcl-x(L) was also unable to prevent the flavopiridol/HDACI regimen from inducing a conformational change in and mitochondrial translocation of Bax, and it did not attenuate Bax dimerization. As a whole, these findings indicate that in contrast to certain conventional cytotoxic agents such as ara-C, overexpression of Bcl-2 or Bcl-x(L) are largely ineffective in preventing perturbations in Bax, mitochondrial injury, and cell death in human leukemia cells subjected to simultaneous CDK and HDAC inhibition. They also raise the possibility that a strategy combining CDK and HDAC inhibitors may be effective against drug-resistant leukemia cells overexpressing Bcl-2 or Bcl-x(L).
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PMID:Flavopiridol and histone deacetylase inhibitors promote mitochondrial injury and cell death in human leukemia cells that overexpress Bcl-2. 3082 53

Spontaneous in vitro apoptosis reflects a true biological heterogeneity between patients which has to be considered when in vitro models are used to study regulation of apoptosis in native human AML cells. Even though the balance between pro- and anti-apoptotic signaling seems to have a prognostic impact in AML, the possible clinical relevance of spontaneous apoptosis remains to be clarified. High apoptosis/low viability was associated with low levels of heat shock proteins 70 and 90 as well as low Bcl-2:Bax ratio for patients heterogeneous with regard to morphology, membrane molecule expression, genetic abnormalities and response to therapy.
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PMID:Stress-induced in vitro apoptosis of native human acute myelogenous leukemia (AML) cells shows a wide variation between patients and is associated with low BCL-2:Bax ratio and low levels of heat shock protein 70 and 90. 1660 Mar 71

To determine the possible roles of survivin in the pathogenesis of myelodysplastic syndrome (MDS) and to explore the relationship between apoptosis and angiogenesis in MDS, the expressions of survivin, Bcl-2 and VEGF were detected in the BM cells of de novo patients with MDS, patients with AML and individuals of control by immunochemical staining and their relationship was analyzed. The results showed that the expression rate and integral of all the three proteins in the low-risk group of MDS, high-risk group of MDS and de novo acute myeloid leukemia patients gradually increased, in addition to expression of Bcl-2 in low-risk group of MDS and control group. The significant differences were observed in every two groups and there were positive relations between the every two proteins. It is concluded that survivin, Bcl-2 and VEGF are all involved in the pathogenesis of MDS, and related with the progression of this disease, the deregulated apoptosis and angiogenesis may be involved in the pathogenesis of MDS through interaction among three proteins mentioned above.
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PMID:[Expressions of survivin, Bcl-2 and VEGF in patients with myelodysplastic syndrome and their relationship]. 1663 95

A novel small molecule inhibitor, 4-(3-methoxy-phenylsulfannyl)-7-nitro-benzofurazan-3-oxide (MNB), competes with the Bak BH3 peptide to bind Bcl-2 protein with a binding affinity of IC(50) = 0.70 microM, as assessed by a fluorescence polarization based binding assay. HL-60 cells express the highest levels of Bcl-2 among the cell lines examined. Treated with 5 microM of MNB only for 6 h, 85% of HL-60 cells were detected to undergo apoptosis. Pan-caspase inhibitor, Z-VAD-FMK, blocks MNB-induced apoptosis in HL-60 cells. Caspase-2, caspase-3, caspase-7, caspase-8, caspase-9, and PARP activation were observed at as early as 4 to 6 h of MNB treatment. In addition, it has been confirmed that the caspase-3 specific inhibitor, Z-DEVD-FMK, blocks the activation of caspase-8 in MNB-treated HL-60 cells. MNB treatment does not change Bcl-2 or Bax expression level in HL-60 cells, but causes Bid cleavage. Further experiments have illustrated that MNB inhibits the heterodimerization of Bcl-2 with Bax or Bid, reduces the mitochondrial membrane potential (DeltaPsimt), and induces cytochrome c release from mitochondria in HL-60 cells. These results suggest that MNB induces apoptosis in HL-60 by inhibiting the heterodimerization of Bcl-2 with pro-apoptosis Bcl-2 members, resulting in a decrease in the mitochondrial membrane potential and cytochrome c release, activation of caspases and PARP; it is a caspase-dependent process in which the activation of caspase-8 is dependent on the mitochondrial apoptosis signal transduction pathway. MNB prolongs the life spans of HL-60 bearing mice, potently kills fresh AML and ALL cells, indicating that it has the potential to be developed to treat leukemia.
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PMID:A novel Bcl-2 small molecule inhibitor 4-(3-methoxy-phenylsulfannyl)-7-nitro-benzofurazan-3-oxide (MNB)-induced apoptosis in leukemia cells. 1739 62

Tetra-O-methyl nordihydroguaiaretic acid (M4N) was shown to induce G2 arrest and suppress human xenograft tumor growth by inhibiting Cdc2 and survivin. We examined the effect of M4N on leukemia and found that M4N inhibited growth and induced cell death in leukemic cell lines and blasts from AML patients. However, no significant changes in Cdc2 and survivin levels and G2 arrest were observed. Cell death and growth inhibition were dependent neither on XIAP, Bcl-2, and Bcl-X(L) levels nor on caspase-8. M4N did not promote cell differentiation in HL-60 cells. Interestingly, significant inhibition of AKT phosphorylation was observed in M4N treated OCI-AML3 cells. Collectively, our data showed that M4N inhibited cell growth and induced cell death in both leukemic cell lines and AML patient sample via a mechanism not mediated by Cdc2 and survivin inhibition and suggested that the extrinsic and the mitochondrial apoptotic pathways are not essential.
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PMID:Tetra-O-methyl nordihydroguaiaretic acid inhibits growth and induces death of leukemia cells independent of Cdc2 and survivin. 1745 37

The potent bioactive sphingolipid mediator, sphingosine-1-phosphate (S1P), is produced by 2 sphingosine kinase isoenzymes, SphK1 and SphK2. Expression of SphK1 is up-regulated in cancers, including leukemia, and associated with cancer progression. A screen of sphingosine analogs identified (2R,3S,4E)-N-methyl-5-(4'-pentylphenyl)-2-aminopent-4-ene-1,3-diol, designated SK1-I (BML-258), as a potent, water-soluble, isoenzyme-specific inhibitor of SphK1. In contrast to pan-SphK inhibitors, SK1-I did not inhibit SphK2, PKC, or numerous other protein kinases. SK1-I decreased growth and survival of human leukemia U937 and Jurkat cells, and enhanced apoptosis and cleavage of Bcl-2. Lethality of SK1-I was reversed by caspase inhibitors and by expression of Bcl-2. SK1-I not only decreased S1P levels but concomitantly increased levels of its proapoptotic precursor ceramide. Conversely, S1P protected against SK1-I-induced apoptosis. SK1-I also induced multiple perturbations in activation of signaling and survival-related proteins, including diminished phosphorylation of ERK1/2 and Akt. Expression of constitutively active Akt protected against SK1-I-induced apoptosis. Notably, SK1-I potently induced apoptosis in leukemic blasts isolated from patients with acute myelogenous leukemia but was relatively sparing of normal peripheral blood mononuclear leukocytes. Moreover, SK1-I markedly reduced growth of AML xenograft tumors. Our results suggest that specific inhibitors of SphK1 warrant attention as potential additions to the therapeutic armamentarium in leukemia.
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PMID:A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia. 1851 10

Citrus flavonoids are reported to be promising bioactive compounds against hyperlipidemia and lipid biosynthesis. However, the mechanism of the lipid lowering effect by flavonoids remains unknown. The present study examines the effect of some flavanones on the adipocytic conversion of the human preadipocyte cell line, AML-I. Among four structure-related flavanones including naringenin, naringenin-7-rhamnoglucoside (naringin), hesperetin, and hesperetin-7-rhamnoglucoside (hesperidin), the aglycones such as naringenin and hesperetin exhibited the growth arrest of AML-I cells. When the cells were examined by Annexin V-FITC staining method, it was noticed that growth arrest was induced by apoptotic cell death. In the study of apoptosis-related protein in the naringenin-treated cells, anti-apoptotic proteins such as p-Akt, NF-kappaB, and Bcl-2 were decreased, and pro-apoptotic protein Bad was accumulated by Western blot analysis. Interestingly, exposure of AML-I cells to naringenin or hesperetin during short-term cultures increased cytoplasmic lipid droplets by Sudan Black B staining. Furthermore, expression of fatty acid synthase (FAS) and peroxisome proliferator activated receptor (PPAR)-gamma was enhanced in naringenin-treated cells. These data suggest that apoptosis by flavanones does not inhibit the adipocytic conversion of AML-I preadipocytes. The result also indicates that adipocyte may not be a direct target for the lipid-lowering activity of the flavanones.
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PMID:Naringenin and hesperetin induce growth arrest, apoptosis, and cytoplasmic fat deposit in human preadipocytes. 1898 Mar 25


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