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)

To study sensitivity of drug resistance indexes and resistance manner in acute myeloid leukemia (AML), MTT drug sensitivity, growth types of CFU-L in vitro, Bcl-2 antigen and Bcl-2/Bax ratio and intracellular fluorescence intensity of daunorubicin (DNR) were determined. In 62 cases of AML, the positive coincidence rate was 73% with MTT test and the negative coincidence rate was 70%. In 3 commonly used drugs, if one drug showed sensitivity, the coincidence remission rate reached 71%. In 51 cases of AML, there were 31 patients in the group of complete remission (CR), in which CFU-L of 29 patients showed independent growth. CFU-L of 2 patients showed no growth. However, there were 20 patients in the group of non-remission (NR), in which CFU-L of 14 patients showed independent growth. CFU-L of 6 patients showed non-growth pattern. Statistical analysis showed significant difference (P < 0.05). In 32 cases of AML, the expression rate of Bcl-2 was 59.55% +/- 19.56% in drug-sensitive group, and one was 77.36% +/- 11.91% in drug-resistant group, respectively (P < 0.05). At the same time, the ratio of Bcl-2/Bax was 7.50 +/- 5.04 in drug-sensitive group and one was 14.32 +/- 8.99 in drug-resistant group, respectively (P < 0.05). In 15 case of clinically drug-resistant AML, the fluorescence histogram of DNR showed left-shift of main peak (LSMP) in 12 patients. They were diagnosed as classical drug resistance. Meanwhile, 1 patient showed right-shift of main peak (RSMP) in 3 patients. They were diagnosed as re-growth drug resistance. It is concluded that MTT and CFU-L might be used for prediction of drug sensitivity or resistance when patients were on treatment. Bcl-2 and ratio of Bcl-2/Bax might be associated with the prognosis. DNR histogram could be employed for identify the pattern drug resistance. The strength and weakness of these techniques were discussed.
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PMID:The comprehensive evaluation on four indices of drug resistance in acute myeloid leukemia. 1284 Aug 92

An internal tandem duplication (ITD) of the juxtamembrane (JM) domain of FLT3 (FLT3/ITD) has been found in 20% of patients with acute myeloid leukemia (AML) and is correlated with leukocytosis and a poor prognosis. Here, we compared the antiapoptotic effects of wild-type FLT3 (WtFLT3) and FLT3/ITD in terms of the regulation of Bcl-2 family members. In a murine myeloid cell line, 32D, interleukin-3 (IL-3) deprivation induced apoptosis following the down-regulation of Bcl-XL and the dephosphorylation of Bad. However, the expression levels of Bcl-2, Bax, Bak, and Mcl-1 were unchanged. In WtFLT3-transfected 32D (WtFLT3-32D) cells, FLT3 ligand (FL) stimulation did not restore the down-regulation of Bcl-XL but maintained the phosphorylation of Bad. Combined treatment with phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, and mitogen-activated protein kinase kinase (MEK) inhibitor, PD98059, dephosphorylated Bad and induced apoptosis in WtFLT3-32D cells stimulated with FL. Induction of nonphosphorylated Bad induced remarkable apoptosis. These findings suggest that the FL stimulation is associated with antiapoptosis through Bad phosphorylation. On the other hand, FLT3/ITD-transfected 32D (FLT3/ITD-32D) cells survived in an IL-3-or FL-deprived state. Furthermore, the dephosphorylation of Bad using LY294002 and PD98059 was insufficient for apoptosis, and the down-regulation of Bcl-XL using antisense treatment was needed to induce apoptosis. FLT3 kinase inhibitor, AG1296, alone not only dephosphorylated Bad but also down-regulated Bcl-XL, leading FLT3/ITD-32D cells into apoptosis. These findings suggest that the antiapoptotic pathways from FLT3/ITD are more divergent than those from WtFLT3 and may represent targets for drug discovery with the potential of inducing selective cell death of human leukemia cells.
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PMID:Different antiapoptotic pathways between wild-type and mutated FLT3: insights into therapeutic targets in leukemia. 1284 96

In order to observe the expression of Fas, FasL and Bcl-2 and apoptosis of bone marrow CD34(+) cells in patients with myelodysplastic syndrome (MDS), and to explore the relation between the expression of these antigens and apoptosis, the expression of Fas, FasL and Bcl-2 and apoptosis of bone marrow CD34(+) cell were evaluated by flow cytometry in 26 patients with MDS including 9 cases of refactory anemia (RA), 1 case of RA with ringed sideroblasts (RAS), 9 cases of RA with excess blasts (RAEB) and 7 cases of RAEB in transformation (RAEB-t), 10 patients with acute myeloid leukemia (AML) and 6 control patients with normal bone marrow. The results showed that the expression of Fas and FasL of CD34(+) cells significantly increased in all types of MDS patients compared with control group (P < 0.01). The expression of Bcl-2 on CD34(+) cells in RAEB and RAEB-t patients was much higher as compared with that in control group (P < 0.01), but there was no significant difference between RA/RAS patients and control group (P > 0.05). The expression rates of Fas on CD34(+) cells were almost identical in all kinds of MDS, but there was significant difference on the expression of Bcl-2 (RA/RAS < RAEB < RAEB-t). Apoptosis of CD34(+) cells significantly increased in RA/RAS and RAEB patients compared with control group (P < 0.01), but there was no difference between RAEB-t and control group. Moreover, apoptosis of CD34(+) cells in control much higher than that in AML group (P < 0.01). There was no correlation between the expression of Fas or FasL and apoptosis on CD34(+) cell of MDS patients. Nevertheless, there was a negative correlation between the expression of Bcl-2 and apoptosis. It is concluded that apoptosis of CD34(+) cells was affected by a lot of factors in MDS, in which Bcl-2 is an important factor of depressing apoptosis. During the progress from MDS to AML, apoptosis changes from overgoing to deficiency in CD34(+) cell.
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PMID:[Expression of Fas, FasL and Bcl-2 and apoptosis of bone marrow CD34+ cells in patients with myelodysplastic syndrome]. 1284 12

Bone-marrow minimal residual disease (MRD) causes relapse after chemotherapy in patients with acute myelogenous leukemia (AML). We postulate that the drug resistance is induced by the attachment of very late antigen (VLA)-4 on leukemic cells to fibronectin on bone-marrow stromal cells. We found that VLA-4-positive cells acquired resistance to anoikis (loss of anchorage) or drug-induced apoptosis through the phosphatidylinositol-3-kinase (PI-3K)/AKT/Bcl-2 signaling pathway, which is activated by the interaction of VLA-4 and fibronectin. This resistance was negated by VLA-4-specific antibodies. In a mouse model of MRD, we achieved a 100% survival rate by combining VLA-4-specific antibodies and cytosine arabinoside (AraC), whereas AraC alone prolonged survival only slightly. In addition, overall survival at 5 years was 100% for 10 VLA-4-negative patients and 44.4% for 15 VLA-4-positive patients. Thus, the interaction between VLA-4 on leukemic cells and fibronectin on stromal cells may be crucial in bone marrow MRD and AML prognosis.
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PMID:Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. 1289 78

In vitro studies demonstrating the induction of programmed cell death by cytotoxic drugs used in anticancer chemotherapy suggested that antileukemic treatment eliminates leukemia cells by apoptosis. We therefore analyzed apoptosis induction and activation of apoptosis signaling molecules in patients receiving remission induction treatment for AML and ALL during the initial phase of leukemia cell reduction. A coexistence of distinct populations of CD34(+) and CD34(-) leukemia cells could be identified. During chemotherapy, CD34(+) leukemia cells were more rapidly depleted than CD34(-) cells. Furthermore, a significant increase in leukemia cell apoptosis ex vivo was detected in CD34(+) cells, while no such increase was observed in the CD34(-) subpopulation, suggesting that CD34(+) leukemia cells are the main targets for apoptosis induction through antileukemic treatment. No alterations in Bax and Bcl-2 expression were found during in vivo chemotherapy, and CD95 expression and sensitivity remained low, indicating the induction of apoptosis independent of the CD95 system or regulation of protein levels of Bax and Bcl-2. The data suggest that analysis of leukemia cell subpopulations is required for further identification of apoptosis signaling molecules relevant for response to treatment and assessment of drug efficacy in vivo and in vitro.
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PMID:Apoptosis induction in peripheral leukemia cells by remission induction treatment in vivo: selective depletion and apoptosis in a CD34+ subpopulation of leukemia cells. 1452 71

The rate of apoptosis as well as expression of Bcl-2 and Bax was evaluated before and after induction therapy in leukocytes of 70 patients with acute myeloblastic leukemia (AML), retrospectively divided into group A (with longer survival) and group B (with shorter survival). We found, that leukocytes of untreated AML patients showed susceptibility to apoptosis similar to control cells. Marked increase in percentage of apoptotic leukocytes was observed after induction therapy exclusively in patients with longer survival, which was accompanied by better normalization of routine hematological parameters. In this group, the Bcl-2/Bax ratio was similar to the control and remained unchanged after treatment. In AML patients with shorter survival, a twofold increase in this ratio was observed both before and after the completion of induction therapy. In both groups of untreated patients, western blot analysis revealed the presence of prominent additional bands reacting with anti-Bcl-2 or anti-Bax antibody, which were undetectable in control leukocytes. After the therapy, these bands disappeared, especially in patients from group A. In conclusion, the lack of therapy-induced enhancement in leukocyte apoptosis, an increased ratio of Bcl-2/Bax as well as persistent presence of abnormal Bcl-2 and Bax protein bands after induction therapy in AML patients may be considered as factors associated with unfavorable clinical outcome.
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PMID:The rate of apoptosis and expression of Bcl-2 and Bax in leukocytes of acute myeloblastic leukemia patients. 1462 86

In past studies, we showed that T cells transduced with retroviral diphtheria immunotoxin (IT) target genes could serve as vehicles for delivering IT to tumors in vivo. We took advantage of the observation that antigen-specific T cells are able to penetrate tumors to design an approach delivering combined cellular and humoral therapy directly to the tumor site. To improve tumor specificity, we selected interleukin (IL)-3 as a ligand because its receptor is selectively overexpressed on myeloid leukemia progenitors. Because Bcl-2 family proteins show structural similarity to diphtheria toxin (DT), we constructed a unique retroviral IT using Bax, a proapoptotic member of the Bcl-2 family, in place of DT. Bax was chosen because several studies showed that its transduction induces lethal apoptosis in different cancers. The retroviral construct for gene therapy included IL-3 positioned downstream of its 80 amino acid leader, and permitted cotranslational protein synthesis of hybrid IL-3/human Bax fusion protein. Other vectors were constructed with IL-3 fused to DT or Pseudomonas exotoxin. Retroviral vectors were used to transiently transduce C8, a CD4(+) T cell clone that specifically recognized FBL-3, a lethal myeloid leukemia. Supernatants collected from transduced cells showed proapoptotic activity and selectively inhibited FBL-3 cells in vitro. Intraperitoneal injection of transduced but not nontransduced C8 into mice with subcutaneous tumors or systemic cancer significantly inhibited tumor growth. These results indicate that retroviral IT made with IL-3 and various toxic proteins may be useful in patients with acute myelogenous leukemia (AML). Furthermore, the Bax construct may be particularly useful as a nonimmunogenic substitute for bacterial toxins in retIT.
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PMID:Retroviral immunotoxin gene therapy of leukemia in mice using leukemia-specific T cells transduced with an interleukin-3/Bax fusion protein gene. 1467 Jan 29

The regulation of apoptosis is an important potential target for anticancer therapy. The mitochondrial Bcl-2 protein inhibits apoptosis and is therefore an important mediator of resistance to treatment with traditional cytotoxic chemotherapy, radiotherapy and monoclonal antibody therapy. Oblimersen (Genasense, Aventis Pharmaceuticals / Genta Inc) is a 18mer antisense-oligonucleotide (ASO), which specifically binds to the first 6 codons of the human bcl-2 mRNA, resulting in degradation and destruction of the mRNA by RNAse H. Subsequently there is a significant decrease of bcl-2 translation. A growing number of preclinical and clinical studies suggests that the combination of cytotoxic therapy with Oblimersen results in synergistic anticancer efficacy in many hematologic and solid tumors. Due to its low toxicity profile, oblimersen is an ideal combination partner with conventional chemotherapy. Three randomized phase-III trials (malignant melanoma, chronic lymphocytic leukemia, multiple myeloma) have recently finished recruitment. The results of these studies will be available by the end of 2003. Based on preclinical data, a lot of nonrandomized phase-II studies on several different tumor types like AML, CML, NHL, prostate cancer and breast cancer are underway. The manipulation of proapoptotic and antiapoptotic factors in favor of proapoptotic factors by inhibition of the bcl-2 protein translation in order to enhance the efficacy of anticancer treatments represents a promising new treatment concept in oncology.
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PMID:[Proapoptotic therapy with oblimersen (bcl-2 antisense oligonucleotide)--review of preclinical and clinical results]. 1471 45

Programmed cell death and survival are controlled by complex pathways, with the anti-apoptotic proteins Bcl-2 and Bcl-X(L) and the pro-apoptotic proteins Bax and Bcl-X(S) being major regulators. Variations in the expression of Bcl-X(S) have been observed in leukemic cells from acute myeloid leukemia (AML) patients and correlated with clinical outcome, but the impact of Bcl-X(S) on molecular pathophysiological mechanisms and the potential role of Bcl-X(S) as a therapeutic target in AML are not yet defined. In order to analyze the functional relevance of Bcl-X(S) in AML, Bcl-X(S) was moderately (2-3 fold) overexpressed in the AML cell lines HL-60 and MO7e by transfection with a tetracycline-regulatable Bcl-X(S) expression system. Increased Bcl-X(S) did not change the rate of spontaneous apoptosis, chemosensitivity to ara-C, or cell cycle kinetics. Further analysis of this unexpected result revealed a compensatory transcriptional upregulation of endogenous anti-apoptotic Bcl-X(L) in MO7e and HL-60, and Bcl-2 in HL-60 cells resulting in increased protein levels. Bax levels were unchanged. Bcl-X(L) and Bcl-2 were found to heterodimerize with Bcl-X(S), thereby providing a possible explanation for the abrogation of its pro-apoptotic function. These results suggest the existence of a regulatory mechanism aimed to protect leukemic cells from pro-apoptotic stimuli.
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PMID:Expression of inducible Bcl-X(S) in myeloid leukemia: compensatory upregulation of Bcl-X(L) and Bcl-2 prevents apoptosis and chemosensitization. 1475 70

In about 30% of the patients with acute myeloid leukemia, activating FLT3 receptor mutations have been identified, often as in-frame internal tandem duplications (ITD) at the juxtamembrane domain of the receptor. FLT3-ITD receptors exhibit constitutive tyrosine kinase activity in the absence of FLT3 ligand (FL) binding, and when expressed in cytokine-dependent cell lines and primary hematopoietic cells suppress programmed cell death and increase cell division. However, the signaling pathways important for transformation, in particular the nuclear targets, are unknown. Here we demonstrate that FLT3-ITD expression in Ba/F3 cells results in activation of Akt and concomitant phosphorylation of the Forkhead family member Foxo3a. Phosphorylation of Foxo proteins through FLT3-ITD signaling promotes their translocation from the nucleus into the cytoplasm, which requires the presence of conserved Akt phosphorylation sites in Forkhead transcription factors and PI3K activity. Induction of Foxo3a phosphorylation by FLT3-ITD receptors in Ba/F3 cells correlates with the suppression of Foxo-target genes p27Kip1 and the proapoptotic Bcl-2 family member Bim. Specifically, FLT3-ITD expression prevents Foxo3a-mediated apoptosis and upregulation of p27Kip1 and Bim gene expression. These data indicate that the oncogenic tyrosine kinase FLT3 can negatively regulate Foxo transcription factors, thereby promoting cell survival and proliferation.
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PMID:FLT3 receptors with internal tandem duplications promote cell viability and proliferation by signaling through Foxo proteins. 1498 46


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