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 accumulation of monoclonal chronic lymphocytic leukemia B (B-CLL) cells may be due to excessive proliferation and longevity. Clinical progression may thus come from a constitutive but altered expression of a number of genes that results in extended B-CLL cells life span, increased proliferative capacity and diminished cell death. B-CLL cells express a number of surface markers that characterise the normal B-cells phenotype. However, B-CLL cells are CD5 positive and most of them also express CD6, surface receptors that are present in just a small subset of normal B-cells. When exploring CD6 function, we found out that cross-linking of CD6 protected B-CLL from anti-IgM-induced apoptosis. CD6 activation blocked anti-IgM- induced Bax(alpha) up-regulation and, by doing so, corrected an imbalance in the Bcl-2/Bax ratio that accompanies apoptosis. Here, we review all surface receptors and cytokines that have been described as participating in the induction or protection of B-CLL apoptosis together with data on chemosensitivity and gene modulation, data on the Fas receptor/Fas ligand system, and the implications of all the latter for B-CLL cell survival.
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PMID:Regulation of B-CLL apoptosis through membrane receptors and Bcl-2 family proteins. 971 57

The activities of 2-chlorodeoxyadenosine (2-CdA) metabolizing enzymes, deoxycytidine kinase (dCK) and cytosolic 5'-nucleotidase (5'-NT) were measured in control and bryostatin 1 treated CLL cells using an EBV-negative WSU-CLL cell line. This cell line was established from a patient with CLL resistant to fludarabine. The results revealed a significant increase in dCK activity in bryostatin 1 treated cells at 48 and 72 h compared with the control. 5'-NT activity decreased significantly at 48 h. The ratio of dCK to 5'-NT activity was significantly increased in bryostatin 1 treated WSU-CLL cells after 48 h. WSU-CLL cells treated with bryostatin 1 exhibited an increase in the percentage of apoptotic and dead cells from control levels of 16% to 40%. This percentage was further increased to 67% following the addition of 11.2 microM 2-CdA to WSU-CLL cells pretreated with bryostatin 1. Results from Western blot analysis indicate that WSU-CLL cells express high levels of Bcl-2, Bcl-xL and c-myc, and a low level of Bax. p53 in untreated WSU-CLL cells is undetectable. WSU-CLL cells treated with bryostatin 1 showed a significant increase in the ratio of Bax to Bcl-2. To demonstrate that the bryostatin 1 mediated enhancement of 2-CdA efficacy was not restricted to in vitro cell culture, we have studied the tumor growth delay of WSU-CLL xenografts treated with placebo, bryostatin 1, 2-CdA, and bryostatin 1 followed by 2-CdA. SCID mice given bryostatin 1 at 75 microg x kg(-1) x d(-1) for 5 days followed by 30 mg x kg(-1) x d(-1) 2-CdA for 5 days in two cycles, had significantly improved tumor growth delay (P = 0.05). We conclude that bryostatin 1 is not only capable of inducing apoptosis by itself, but also sensitizes de novo resistant WSU-CLL cells to the chemo-therapeutic effects of 2-CdA. The bryostatin 1-induced increased ratio of dCK/5'-NT activity and an increased ratio of Bax/Bcl-2 are at least two mechanisms through which this natural compound is able to potentiate the anti-tumor activity of 2-CdA in otherwise resistant CLL cells.
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PMID:Potentiation of 2-chlorodeoxyadenosine activity by bryostatin 1 in the resistant chronic lymphocytic leukemia cell line (WSU-CLL): association with increased ratios of dCK/5'-NT and Bax/Bcl-2. 982 May 86

Cross-linking of the CD40 receptors has been shown to induce protein tyrosine kinases (PTK) phosphorylation and prevent apoptosis in Bcl-2 negative germinal center B cells. The expression of CD40 on B chronic lymphocytic leukemia (B-CLL) cells was found to be similar to that of normal B cells. Activation of normal B cells with soluble anti-CD40 monoclonal antibody (mAb) induced tyrosine phosphorylation, prolonged survival and prevented apoptosis. However, activation of CD40 on B-CLL cells using soluble anti-CD40 mAb does not influence survival or apoptosis. Normal B cells entered apoptosis when cultured in the presence of soluble anti-CD95 mAb. This process was independent of PTK activity. On B-CLL cells, the CD95 molecules were downregulated and a transient PTK signal was observed when cross-linking of the receptor by soluble anti-CD95 mAb occurred. Interestingly, B-CLL cells did not enter apoptosis in the presence of anti-CD95 mAb. Our study indicates that survival signals mediated through the CD40 molecule and death signals mediated through the CD95 molecule used different intracellular pathways in control donor B cells. In contrast, B-CLL cells do not respond to these signals. The leukemic B cells showed a defective CD40-mediated signal transduction and downregulated CD95 receptor expression. As a consequence, no apoptosis could be induced in B-CLL cells by a soluble anti-CD95 mAb. The abnormalities of these receptors may contribute to the long-lived status of B-CLL cells.
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PMID:Downregulation of the CD95 receptor and defect CD40-mediated signal transduction in B-chronic lymphocytic leukemia cells. 982 Jun 34

We report the establishment and characterization of two cell lines, MEC1 and MEC2, that grew spontaneously on two subsequent occasions from the peripheral blood (PB) of a patient with B-chronic lymphocytic leukemia (B-CLL) in prolymphocytoid transformation. The patient was EBV-seropositive, his leukemic cells were EBNA negative, but the spontaneously grown cell lines are EBNA-2 positive. In liquid culture MEC1 cells grow adherent to the vessel wall and as tiny clumps; MEC2 cells do not adhere and form large clumps. The doubling time of MEC1 is 40h and of MEC2 is 31h. Both cell lines express the same light (kappa) and heavy chains (mu, delta) as the fresh parental B-CLL cells at the same high intensity, share the expression of mature B cell markers (CD19, CD20, CD21, CD22), differ in the expression of CD23 and FMC7, are CD11a+, CD18+, CD44+, CD49d+, CD54+ and express at high levels both CD80 and CD86. CD5 is negative on MEC1 cells (as on the vast majority of parental cells) and it has been lost by MEC2 cells after several months of culture. The cells have a complex karyotype. The tumour origin of MEC1 and MEC2 has been demonstrated by Southern blot analysis of the IgH loci and by Ig gene DNA sequencing. They use the VH4 Ig family and have not undergone somatic mutations (94.8% homology with germline Ig gene 4-59). Cytofluorographic analysis and RT-PCR reveal that MEC1 and MEC2 overexpress Bcl-2 together with Bax, express large amounts of Bcl-xL and trace amounts of Bcl-xS.
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PMID:MEC1 and MEC2: two new cell lines derived from B-chronic lymphocytic leukaemia in prolymphocytoid transformation. 1007 Nov 28

Our previous data have shown that high Bct-2/ Bax ratios in chronic lymphocytic leukaemia (B-CLL) correlate with in vitro apoptosis and clinical resistance. We have now monitored the in vitro viability of B-CLL cells in relation to Bcl-2 and Bax expression over a 48 h time course following exposure to chlorambucil. The results showed that Bax up-regulation was essential for chlorambucil-induced apoptosis in B-CLL cells and a 3-fold increase in expression within 4 h of exposure to drug was typically observed in sensitive cells; resistant cells failed to up-regulate Bax at all. In contrast, the constitutively high levels of Bcl-2 found in B-CLL cells were found to be down-regulated in apoptotic cells but the mean Bcl-2 expression in viable cells was increased, probably as a result of the loss of lower Bcl-2-expressing cells into the apoptotic compartment. Taken together, these data add further weight to the suggestion that Bcl-2/Bax ratios may be pivotal in determining the fate of B-CLL cells. Furthermore, the Bcl-2/Bax ratios found in apoptotic B lymphocytes were remarkably similar in the treated, untreated and normal control cells, which suggests that there is a universal Bcl-2/Bax ratio threshold for cell survival and cell death.
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PMID:Chlorambucil resistance in B-cell chronic lymphocytic leukaemia is mediated through failed Bax induction and selection of high Bcl-2-expressing subclones. 1008 98

WSU-CLL is a de novo fludarabine resistant cell line established from a patient with advanced chronic lymphocytic leukemia (CLL) refractory to chemotherapy including fludarabine (Flud). Our previous studies indicate that bryostatin 1 (Bryo 1) induces differentiation of WSU-CLL and increases the ratio of dCK/5'-NT activity and Bax/Bcl-2. This study tests the hypothesis that Bryo 1-differentiated cells are more susceptible to Flud than the parent WSU-CLL cells. Flud, given sequentially after Bryo 1, in vitro and in vivo animal studies resulted in significantly higher rates of growth inhibition and improved animal survival. Flud at 100 to 600 nM exhibited a dose-dependent growth inhibitory effect on the WSU-CLL cell line. The sequential exposure to Bryo 1 (10 nM for 72 h) followed by Flud (100 nM) resulted in significantly higher rates of growth inhibition than either the reverse addition of these two agents or each agent alone, but was not significantly different than the concurrent addition of Bryo 1 + Flud. Using 7-amino-actinomycin D staining and flow cytometry, apoptosis was seen in 40.8% of cells treated with Bryo 1 (10 nM, 72 h) followed by Flud, compared with Flud (100 nM, 72 h) followed by Bryo 1 (18.1%). To demonstrate that Bryo 1 enhancement of Flud efficacy was not restricted to in vitro culture, we used the WSU-CLL xenograft model in mice with severe combined immune deficiency (SCID). Bryo 1 + Flud at the maximum tolerated doses (75 microg/kg i.p. and 200 mg/kg i.v., respectively) were administered to mice in different combinations. The survival in days, the tumor growth inhibition ratio (T/C), the tumor growth delay (T-C) in days, log10 kill, as well as mean tumor weight (mtw) of mice treated with Bryo 1 followed by Flud, were significantly better than control and other groups. T/C%, T-C, log10 kill and mtw were as follows: Bryo 1 (36.8%, 10 days, 0.8, 375 mg); Flud (100%, 0. 0 day, 0.0, 1130 mg); Bryo 1 + Flud (14.3%, 12 days, 0.95, 288 mg); Bryo 1 followed by Flud (4.6%, 17 days, 1.35, 35 mg); Flud followed by Bryo (40.3%, 10 days, 0.80, 175 mg). We conclude that: i) Bryo 1 sensitizes WSU-CLL cells to Flud and enhances apoptosis; ii) the sequential treatment with Bryo 1 followed by Flud resulted in higher anti-tumor activity compared with either agent alone, in combination, or the reverse addition of these agents and iii) these results are comparable to those of Bryo 1 followed by 2-CdA suggesting common pathway(s) of interaction between Bryo 1 and purine analogues.
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PMID:Treatment of a de novo fludarabine resistant-CLL xenograft model with bryostatin 1 followed by fludarabine. 1020 Mar 46

Glucocorticoids and fludarabine are able to induce typical features of apoptosis in CLL lymphocytes. Cysteinyl aspartate specific proteases (caspases) play a key biochemical role in the apoptotic pathway. Caspase activation following cytotoxic stimuli leads to highly specific proteolytic cleavage of functionally important cellular enzymes. One of them is poly ADP-ribose) polymerase (PARP). To some extent caspase activation seems to be under the control of the Bcl-2 family of interacting proteins. We determined the role of Bcl-2-family proteins Bcl-2 (anti-apoptotic) and Bax (pro-apoptotic), activation of caspase-3 (CPP32/Yama) and activation of PARP in CLL apoptosis. All 21 analyzed CLL samples expressed Bcl-2 and Bax. Four of 13 (31%) samples with a low Bcl-2/Bax ratio exhibited in vitro prednisolone resistance, whereas eight of nine (88%) samples with a high Bcl-2/Bax ratio were in vitro resistant (</=0.025). There was no significant correlation between clinical pre-treatment status and Bcl-2/Bax ratio. Caspase-3/CPP32 activity increase was registered after dexamethasone as well as after fludarabine treatment in CLL lymphocytes in vitro. Caspase inhibitor Z-VAD.fmk was only able to partially block dexamethasone-induced and spontaneous apoptosis but not fludarabine-induced apoptosis in CLL lymphocytes. PARP activity decreased after dexamethasone and fludarabine treatment. PARP inhibitor 3-aminobenzamide (3-AB) was able to partially inhibit dexamethasone-induced apoptosis but not fludarabine-induced and spontaneous apoptosis.
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PMID:Drug-induced apoptosis in chronic lymphocytic leukemia. 1055 65

Research in chronic lymphocytic leukemia (CLL) has undergone a resurgence of interest in the last decade. While it is obvious that most patients with CLL have typical mature B cells, a number of variants such as splenic lymphoma villous lymphocytes, mantle cell leukemia, and prolymphocytic leukemia need to be considered in the differential diagnosis. This can be established by immunophenotype studies and morphology. Cytogenetic abnormalities are emerging as being of interest, with abnormalities in chromosomes 11 and 17 having major prognostic significance. Immune disregulation is complicated in that along with hypergammaglobulinemia and T-cell dysfunction, the emergence of antibodies directed against hematopoietic cells causes autoimmune hemolytic anemia, neutropenia, and thrombocytopenia. A number of prognostic factors are emerging as being more influential in prognosis and stage, such as serum beta2-microglobulin and soluble CD23. Apoptosis dysregulation is a major feature of CLL, and while no clear pattern has emerged, abnormal levels of bcl2 are common in CLL and bcl2 to bax ratios are also commonly disturbed. Bcl1 levels are commonly increased. Treatment has changed radically. The purine analogs have been demonstrated to be the most active group of drugs in CLL. Combinations of purine analogs, such a fludarabine or 2-chlorodeoxyadenosine, with alkylating agents are emerging as new treatments. The most recent development has been the emergence of two monoclonal antibodies, rituximab (Rituxan; IDEC Pharmaceuticals, San Diego, CA, and Genentech, Inc, San Francisco, CA; directed against CD20) and Campath-1H (directed against CD52 in CLL). The activity of rituximab in lymphoma has been less prominent in small lymphocytic lymphoma (the lymphomatous counterpart of CLL) and this has led to dose escalation studies in CLL with a good level of response. Campath-1H is emerging as another major antibody with marked effect against disease, particularly in the blood and bone marrow. Autologous, allogeneic, and mini-transplant are also being explored extensively. The prognosis for patients with CLL is changing as these new treatments become available.
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PMID:Chronic lymphocytic leukemia. 1056 Oct 25

Over the past decade, the involvement of tyrosine kinases in signal transduction pathways evoked by cytokines has been intensively investigated. Only relatively recently have the roles of serine/threonine kinases in cytokine-induced signal transduction and anti-apoptotic pathways been examined. Cytokine receptors without intrinsic kinase activity such as interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and the interferons were thought to transmit their regulatory signals primarily by the receptor-associated Jak family of tyrosine kinases. This family of tyrosine kinases activates STAT transcription factors, which subsequently transduced their signals into the nucleus to modulate gene expression. Cytokine receptors with intrinsic tyrosine kinase activity such as c-Kit were initially thought to transduce their signals independently of serine/threonine kinase cascades. Recently, both of these types of receptor signaling pathways have been shown to interact with serine/threonine kinase pathways as maximal activation of these tyrosine kinase regulated cascades involve serine/threonine phosphorylation modulated by, for example MAP kinases. A common intermediate pathway initiating from cytokine receptors is the Ras/Raf/MEK/ERK (MAPK) cascade, which can result in the phosphorylation and activation of additional downstream kinases and transcription factors such as p90Rsk, CREB, Elk and Egr-1. Serine/threonine phosphorylation is also involved in the regulation of the apoptosis-controlling Bcl-2 protein, as certain phosphorylation events induced by cytokines such as IL-3 are anti-apoptotic, whereas other phosphorylation events triggered by chemotherapeutic drugs such as Paclitaxel are associated with cell death. Serine/threonine phosphorylation is implicated in the etiology of certain human cancers as constitutive serine phosphorylation of STATs 1 and 3 is observed in chronic lymphocytic leukemia and can be inhibited by the chemotherapeutic drug fludarabine. Serine/threonine phosphorylation also plays a role in the etiology of immunodeficiencies. Activated STAT5 proteins are detected in reduced levels in lymphocytes recovered from HIV-infected individuals and immunocompromised mice. Serine/threonine phosphorylation may be an important target of certain chemotherapeutic drugs which recognize the activated proteins. This meeting report and mini-review will discuss the interactions of serine/threonine kinases with signal transduction and apoptotic molecules and how some of these pathways can be controlled by chemotherapeutic drugs. Leukemia (2000) 14, 9-21.
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PMID:Serine/threonine phosphorylation in cytokine signal transduction. 1063 71

A number of studies revealed that high expression of the proto-oncogene bcl-2 correlated with poor prognosis or resistance to chemotherapy in some tumors but predicted a favorable clinical course in other neoplasias. In these studies, however, different immunologic techniques for Bcl-2 detection were used, raising the question of whether the methods applied were comparable. Using chronic lymphocytic leukemia (CLL) cells, the aims of our study were as follows: (1) to determine the reproducibility of Bcl-2 semiquantitation by immunocytochemistry, flow cytometry, or immunoblotting; (2) to study the agreement between results obtained by these methods; and (3) to examine the association between Bcl-2 expression in tumor cells of 99 patients with CLL and clinical parameters. We found that determination of Bcl-2 expression by immunocytochemistry was reproducible and the results were comparable with those of flow cytometry and immunoblotting. In the patient collective examined, Bcl-2 expression did not reflect the extent of tumor mass, but higher levels were found more often in patients with progressive disease.
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PMID:Analysis of Bcl-2 protein expression in chronic lymphocytic leukemia. A comparison of three semiquantitation techniques. 1066 24


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