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)

Signal transduction and apoptosis in B-cell chronic lymphocytic leukemia (CLL) cells with a post-germinal center (GC) phenotype were studied. Specific activation of the cells was induced by a combination of soluble anti-CD40 monoclonal antibody and interleukin-4 (CD40/IL-4) and nonspecific activation with a combination of phytohemagglutinin, phorbol-12-myristate-13-acetate and ionomycin (chemical mixture). Less than 5% of these leukemia cells entered the cell cycle after activation, as indicated by the number of cells in G0/G1 phase. The protein tyrosine phosphorylation pattern and expression of the Bcl-2 protein were specific in ex vivo CLL cells of each individual patient. Expression of the p53 protein was not detectable in these leukemia cells. Cross-linking of the CD40/IL-4 receptors on CLL cells significantly upregulated phosphotyrosine proteins and the p53 protein. In the presence of chemical mixture, downregulated phosphotyrosine proteins were detected. Alterations in Bcl-2 expression were independent of cross-linking with CD40/IL-4 or chemical mixture. A high frequency of apoptotic cells was detected in cells that had downregulated phosphotyrosine proteins and Bcl-2 protein. There was no correlation between induction of apoptosis and expression of p53 protein. Our results suggest that apoptosis in resting leukemia cells could occur prior to the cell cycle progression. Alterations in phosphotyrosine proteins and Bcl-2 but not p53 might play an important role in the regulation of apoptosis in resting G0/G1 memory post-GC B-CLL cells.
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PMID:Significance of phosphotyrosine proteins, Bcl-2 and p53 for apoptosis in resting B-chronic lymphocytic leukemia (CLL) cells. 1177 86

B-cell chronic lymphocytic leukemia is characterized by the accumulation of malignant B lymphocytes as a result of abnormal survival signals operating in vivo. Previously, we showed that adhesion of B-CLL cells to the fibronectin fragment H89, a ligand for alpha4beta1 integrin, prevents their spontaneous apoptosis in vitro. We have now studied whether alpha4beta1/H89 interaction affected the response of B-CLL cells to the therapeutic drug fludarabine. B-CLL cells cultured on H89 during treatment with fludarabine showed significantly higher mean viability (P<0.05) than cells cultured on the control polylysine for all doses of drug tested. Similar results were obtained with the EHEB cell line. Analysis of the expression of Bcl-2-family proteins after 48 h of fludarabine treatment revealed that Bcl-xL levels were significantly higher (P<0.05) for cells cultured on H89 than on polylysine and correlated (r=0.56, P<0.05) with the increased cell viability observed on H89 cultures. These results indicate that Bcl-xL is involved in the survival signals induced by alpha4beta1 ligation and may contribute to the progressive drug resistance observed in B-CLL.
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PMID:Engagement of alpha4beta1 integrin by fibronectin induces in vitro resistance of B chronic lymphocytic leukemia cells to fludarabine. 1186 87

We evaluated cells from 24 patients with B cell chronic lymphocytic leukemia (B-CLL) to determine apoptosis induced by CD5 hypercross-linking. Following the CD5 hypercross-linking with anti-CD5 monoclonal antibodies (MoAbs), we identified 10 patients where CD5 hypercross-linking induced apoptosis (group A) and 14 patients whose cells were resistant to the anti-CD5 MoAbs (group B). The programmed cell death pathway of the cells from patient group A was caspase-3 and poly (ADP-ribose) polymerase (PARP)-dependent, involved a reduction of the mitochondrial transmembrane potential DeltaPsi and a down-regulation of the anti-apoptotic Bcl-2, Mcl-1 and iNOS proteins. Early activation-associated molecules such as CD25 and CD69 were expressed at higher levels than in controls after 6 h of culture with anti-CD5 MoAb. The expression of CD5 and of CD72, the ligand for CD5, were significantly lower in group A compared with group B. Anti-CD20 MoAb had similar activity with anti-CD5 MoAb and the combination of the two MoAbs seemed to be additive. In this study, it is suggested that the cells from some B-CLL patients can be induced into programmed cell death by CD5 hypercross-linking with anti-CD5 MoAbs.
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PMID:Apoptosis induction by hypercross-linking of the surface antigen CD5 with anti-CD5 monoclonal antibodies in B cell chronic lymphocytic leukemia. 1189 36

Trans-resveratrol was analysed for its apoptotic and growth inhibitory activity in human B-cell lines derived from chronic B-cell malignancies (WSU-CLL and ESKOL), and in leukaemic lymphocytes from patients with B-cell chronic lymphocytic leukaemia (B-CLL). Resveratrol displayed antiproliferative activity on both B-cell lines, as estimated by the decrease in cell recovery and inhibition of thymidine uptake. Furthermore, resveratrol induced apoptosis in the two cell lines as well as in B-CLL patients' cells, as evidenced by the increase in annexin V binding, caspase activation, DNA fragmentation and decrease of the mitochondrial transmembrane potential DeltaPsim. We previously reported that nitric oxide (NO), endogenously released by an iNO synthase (iNOS) spontaneously expressed in these leukaemic cells, contributed to their resistance towards apoptosis. We show here that resveratrol inhibited both iNOS protein expression and in situ NO release in WSU-CLL, ESKOL and B-CLL patients'cells. In addition, Bcl-2 expression was also inhibited by resveratrol. Thus, downregulation of the two anti-apoptotic proteins iNOS and Bcl-2 can contribute to the apoptotic effects of resveratrol in leukaemic B cells from chronic leukaemia. Our data suggest that this drug is of potential interest for the therapy of B-CLL.
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PMID:Analysis of resveratrol-induced apoptosis in human B-cell chronic leukaemia. 1206 Jan 19

The role of Bax and Bak, 2 proapoptotic proteins of the Bcl-2 family, was analyzed in primary B-cell chronic lymphocytic leukemia (CLL) cells following in vitro treatment with fludarabine, dexamethasone, or the combination of fludarabine with cyclophosphamide and mitoxantrone (FCM). A strong correlation was found between the number of apoptotic cells and the percentage of cells stained with antibodies recognizing conformational changes of Bax (n = 33; r = 0.836; P <.001) or Bak (n = 10; r = 0.948; P <.001). Preincubation of CLL cells with Z-VAD.fmk (N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone), a broad caspase inhibitor, abolished caspase-3 activation, exposure of phosphatidylserine residues, and reactive oxygen species generation; partially reversed the loss of transmembrane mitochondrial potential (DeltaPsim); but did not affect Bax or Bak conformational changes. These results indicate that the conformational changes of Bax and Bak occur upstream of caspase activation or are caspase independent. Following drug-induced apoptosis, Bax integrates into mitochondria, as demonstrated by fluorescence microscopy and Western blot, without changes in the total amount of Bax or Bak protein. Fludarabine and FCM induce p53 stabilization, but do not seem to be essential in inducing Bax and Bak conformational changes, as they are also observed in dexamethasone-treated CLL cells. These results demonstrate that, in CLL cells, the change in the intracellular localization of Bax from cytosol to mitochondria and the conformational changes of Bax and Bak are among the early steps in the induction of cell death.
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PMID:Spontaneous and drug-induced apoptosis is mediated by conformational changes of Bax and Bak in B-cell chronic lymphocytic leukemia. 1217 4

We have recently described a novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (CD437/AHPN) that induces apoptosis in a number of malignant cell types. We now describe our studies examining the effects of CD437 and a nonretinoidal analog (MM002) on the in vitro proliferation of the ALL-REH cell line, the in vitro and in vivo growth of a novel Epstein-Barr virus-negative (EBV(-)) B-cell chronic lymphocytic leukemia (B-CLL) cell line (WSU-CLL), and primary cultures of human B-CLL and acute lymphoblastic leukemia (ALL) cells. CD437 and MM002 induce apoptosis in both cell lines, as indicated by the activation of caspase-2 and caspase-3, cleavage of poly(adenosine diphosphate-ribose) (poly(ADP-ribose)) polymerase, increase in annexin V binding, and subsequent nuclear fragmentation. CD437-mediated apoptosis was not associated with the modulation of Bcl-2, Bax, or Mcl-1 levels, but was associated with the cleavage of the antiapoptotic protein Bcl-X(L) to a proapoptotic 18-kD form. This cleavage of Bcl-X(L) was dependent on caspase-3 activation since Bcl-X(L) cleavage and apoptosis were inhibited by the caspase-3 inhibitor Z-DVED-fmk. CD437 markedly inhibited the growth of WSU-CLL cells in severe combined immunodeficiency (SCID) mice. Tumor growth inhibition, growth delay, and log cell kill were 85.7%, 21 days, and 2.1, respectively, in the treated mice. Moreover, 1 of the 5 treated mice was tumor-free longer than 150 days and thus was considered cured. Exposure of primary cultures of both B-CLL and ALL cells obtained from patients to CD437 and MM002 resulted in their apoptosis. These results suggest that CD437 and MM002 analogs may have a potential role in the treatment of B-CLL and ALL.
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PMID:Induction of apoptosis of human B-CLL and ALL cells by a novel retinoid and its nonretinoidal analog. 1235 3

In B-cell chronic lymphocytic leukemia (CLL) a high Bcl-2/Bax ratio contributes to death defiance. We sought to identify any genetic changes in the BAX as a possible mechanism for its altered expression in CLL. The BAX gene from the RL cell line and B-cells from 34 CLL patients and 25 controls were sequenced. A novel heterozygous G(-248)A polymorphism in the 5'-UTR was present in 69% of stage I-IV patients and 5.5% of stage 0 patients, and in 4.0% of controls. It was associated with reduced protein expression (P=0.049), progression beyond Rai stage 0 (P=0.00018) and failure to achieve complete response (P=0.038).
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PMID:Association of a novel single nucleotide polymorphism, G(-248)A, in the 5'-UTR of BAX gene in chronic lymphocytic leukemia with disease progression and treatment resistance. 1235 69

The aim of this study was to investigate the effects of all-trans retinoic acid (ATRA) on apoptosis induction, Bcl-2 family protein expression, and differentiation in B-cell chronic lymphocytic leukaemia (B-CLL) cells. ATRA induced apoptosis in all the B-CLL samples tested, and this was accompanied by a specific reduction in Bcl-2 and Mcl-1 protein expression in the apoptotic cells. In contrast, Bax, p21, and p53 expression was not altered in either the viable or apoptotic B-CLL cells, inferring that ATRA utilises a p53-independent cell death pathway. Caspase-3 activation was shown to be a prerequisite for ATRA-induced apoptosis, which was inhibited by the pan-caspase inhibitor Z-VAD-FMK and the caspase-9 inhibitor Z-LEHD-FMK. In addition, the retinoic acid receptor (RAR) antagonist AGN194310 failed to abrogate the apoptotic effects of ATRA, indicating that RAR binding was not necessary for ATRA-induced apoptosis. Furthermore, there was no evidence of ATRA-induced differentiation of the B-CLL cells in this study either in terms of altered morphology or immunophenotype. In summary these data indicate that ATRA induces apoptosis via the intrinsic apoptotic pathway, and this is independent of RAR binding, p53 activation, and cellular differentiation in B-CLL cells.
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PMID:Retinoid-induced apoptosis in B-cell chronic lymphocytic leukaemia cells is mediated through caspase-3 activation and is independent of p53, the retinoic acid receptor, and differentiation. 1243 Dec 42

EB1089, a novel vitamin D3 analog, has been shown to have cytotoxic and antiproliferative properties in a variety of malignant cells. However, its potential as a treatment for B-cell chronic lymphocytic leukemia (B-CLL) has not been evaluated. EB1089 induced apoptosis in all of the 102 B-CLL samples tested with a mean LD(50) (the concentration of EB1089 required to kill 50% of cells) value (+/- SD) of 2.1 x 10(-8) M (+/- 1.4 x 10(-8) M). Furthermore, no significant difference was found in the cytotoxicity of EB1089 in B-CLL samples from previously treated and untreated patients (P =.1637). Induction of apoptosis was associated with a reduction in Bcl-2 and Mcl-1 protein expression, but this was evident only in the apoptotic cells. In contrast, the expression of Bax, p21, and p53 was not altered in the viable or apoptotic cells from either B- or T-lymphocyte lineages. EB1089-induced apoptosis was preceded by activation of p38 mitogen-activated protein (MAP) kinase and suppression of extracellular signal-regulated kinase (ERK) activity, and this was associated with downstream activation of caspase-3. The pancaspase inhibitor (Z-VAD-FMK) and the caspase-9 inhibitor (Z-LEHD-FMK) were able to partially abrogate the apoptotic effects of EB1089 but did not affect the phosphorylation of p38 MAP kinase or the suppression of ERK. The B-CLL cells in the study were shown to highly express vitamin D receptor, but an additional receptor-independent mechanism of cell killing cannot be ruled out at this stage. These findings show that EB1089 is a potent apoptosis-inducing agent in B-CLL cells and may be useful in the treatment of B-CLL patients, particularly those with p53 mutations or drug-resistant disease.
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PMID:The vitamin D3 analog EB1089 induces apoptosis via a p53-independent mechanism involving p38 MAP kinase activation and suppression of ERK activity in B-cell chronic lymphocytic leukemia cells in vitro. 1244 53

Our previous work demonstrated that antisense oligonucleotides complementary to Bcl-2 mRNA sequences were able to reduce Bcl-2 protein expression in B-cell chronic lymphocytic leukaemia (B-CLL) cells. Furthermore, the reduction in Bcl-2 expression led to an increase in apoptotic cell death that was associated with an increase in Bax expression. In this present study antisense oligonucleotides directed towards the Bax translation initiation sequence were employed to determine whether Bcl-2 and Bax protein expression were interdependent upon one another and whether Bcl-2 antisense-induced apoptosis was mediated through a p53-dependent cell death pathway. The antisense oligonucleotide down-regulated Bax protein expression between 23.7 and 68.8% in the 20 B-CLL samples tested and significantly inhibited apoptotic cell death when compared to controls (p = 0.0001). Furthermore, these changes were independent of Bcl-2 expression suggesting that the previously observed increase in Bax expression following exposure of B-CLL cells to Bcl-2 antisense oligonucleotides was probably caused by the induction of apoptosis rather than a rheostatic response to the reduction in Bcl-2 protein expression. This notion was substantiated by the fact that p21 expression was induced in Bcl-2 antisense-treated B-CLL cells, a finding consistent with p53 activation.
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PMID:Antisense oligonucleotides complementary to Bax transcripts reduce the susceptibility of B-cell chronic lymphocytic leukaemia cells to apoptosis in a bcl-2 independent manner. 1248 99


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