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)

Arsenic trioxide (As(2)O(3)) has been used successfully in the treatment of acute promyelocytic leukemia. However, effects of As(2)O(3) in normal peripheral blood T cells have not been studied in detail. The purpose of this study was to investigate whether As(2)O(3) would induce apoptosis in normal T cells and therefore may have immunosuppressive side effects. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated nick end labeling assay, caspase activation by flow cytometry and colorimetric assay, mitochondrial transmembrane potential (deltapsi(m)), intracellular reactive oxygen species (ROS), and intracellular reduced glutathione (GSH) by flow cytometry. The release of cytochrome c and apoptosis-inducing factor (AIF) from the mitochondria was measured by confocal microscopy, and the expression of molecules regulating apoptosis was measured by Western blotting. As(2)O(3), at clinically achievable therapeutic concentrations, induces apoptosis in peripheral blood T cells. As(2)O(3)-induced apoptosis was associated with reduced deltapsi(m), enhanced generation of intracellular ROS, decreased levels of intracellular GSH, release of cytochrome c and AIF from the mitochondria, activation of caspases, down-regulation of Bcl-2 and Bcl-x(L), and up-regulation of Bax expression. In addition, exogenous GSH protected lymphocytes from As(2)O(3)-induced apoptosis. Furthermore, overexpression of Bcl-2 inhibited As(2)O(3)-induced apoptosis and blocked depolarization of deltapsi(m), generation of ROS, and release of both cytochrome c and AIF. These data indicate that As(2)O(3) induces apoptosis in T cells by enhancing oxidative stress and that Bcl-2 appears to play a major role in As(2)O(3)-induced apoptosis.
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PMID:Arsenic trioxide induces apoptosis in peripheral blood T lymphocyte subsets by inducing oxidative stress: a role of Bcl-2. 1293 60

Arsenic trioxide (ATO) and paclitaxel (TAXOL) are effective in the treatment of various types of cancers. Both drugs induce G2/M arrest. We have previously shown that ATO is a potent inducer of apoptosis in myeloma cells expressing mutant p53 engaging both the intrinsic and extrinsic apoptotic pathways. Here we compared the effect of ATO and TAXOL on myeloma cells expressing mutant p53 and varying levels of Bcl-2. ATO rapidly induced Apo2/TRAIL, activation of caspase 8, cleavage of BID, depolarization of mitochondrial membrane (MM) and release of AIF from mitochondria in a Bcl-2 independent fashion. Apoptosis was associated with early formation of ring-like perinuclear condensed chromatin colocalized with AIF. In contrast, paclitaxel-induced apoptosis MM depolarization, cytochrome C release and activation of caspase 9 were all blocked by Bcl-2. Apoptosis was associated with a random chromatin condensation and nuclear fragmentation with no early involvement of AIF.
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PMID:Arsenic trioxide and paclitaxel induce apoptosis by different mechanisms. 1472 46

The article highlighted in this issue is "Reversal of Bcl-2 Mediated Resistance of the EW36 Human B-Cell Lymphoma Cell Line to Arsenite and Pesticide-Induced Apoptosis by PK11195, a Ligand of the Mitochondrial Benzodiazepine Receptor" by Donna E. Muscarella, Kerry A. O'Brien, Ann T. Lemley, and Stephen E Bloom from Cornell University in Ithaca, NY (pp. 66-73). The following brief review summarizes their findings, highlights the novel biological model and experimental approach used, and explores potential mechanistic and therapeutic implications of these findings.
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PMID:The mitochondrial benzodiazepine receptor as a potential target protein for drug development: demonstration of functional significance with cell lines exhibiting differential expression of Bcl-2. 1273 Jun 27

Arsenic trioxide is valuable for treatment of promyelocytic leukemia, but less attention has been paid to its therapeutic potential for other cancers. In this study, the effects of arsenic trioxide were tested in human pancreatic (AsPC-1), colonic (HT-29), and breast (MCF-7) cancer cells. In all three cancer cell lines, arsenic trioxide inhibited proliferation in a concentration and time-dependent manner, as measured by 3H-methyl thymidine incorporation and cell counting. Coincident with inhibition of growth, arsenic trioxide induced marked morphologic changes, including reduced cytoplasmic volume, membrane blebbing, and nuclear condensation consistent with apoptosis. Propidium iodide DNA staining at 24 hours revealed cell cycle arrest in the G0/G1 phase and an increase in the S phase, while at 72 hr there was G2/M phase arrest with a marked increase in the sub-G0/G1, apoptotic cell population. The DNA fragmentation induced by arsenic trioxide was confirmed by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay in all cell lines. Western blot analysis revealed activation of caspase -3, -7, and -9 by arsenic trioxide. Caspase-3 activity was confirmed by demonstrating cleavage of its downstream target, poly ADP-ribose polymerase (PARP). Expression of the antiapoptosis protein, Bcl-2, was time-dependently decreased. In contrast, arsenic trioxide markedly enhanced the expression of the p21 protein, GADD45 and GADD153, in a time-dependent manner. These findings suggest that arsenic trioxide has potential as a therapeutic agent for these cancers.
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PMID:Arsenic trioxide causes redistribution of cell cycle, caspase activation, and GADD expression in human colonic, breast, and pancreatic cancer cells. 1549 60

Arsenic trioxide (As(2)O(3)) has shown considerable efficacy in treating hematological malignancies with induction of programmed cell death (PCD) type I, apoptosis. However, the mechanisms underlying the antitumor effect of As(2)O(3) on solid tumors are poorly defined. Previously, we reported that As(2)O(3) induced autophagic cell death (PCD type II) but not apoptosis in human malignant glioma cell lines. The purpose of this study was to elucidate the molecular pathway leading to autophagic cell death. In this study, we demonstrated that the cell death was accompanied by involvement of autophagy-specific marker, microtubule-associated protein light chain 3 (LC3), and damage of mitochondrial membrane integrity, but not by caspase activation. Analysis by cDNA microarray, RT-PCR, and Western blot showed that cell death members of Bcl-2 family, Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3) and its homologue BNIP3-like (BNIP3L), were upregulated in As(2)O(3)-induced autophagic cell death. Exogenous expression of BNIP3, but not BNIP3L, induced autophagic cell death in malignant glioma cells without As(2)O(3) treatment. When upregulation of BNIP3 induced by As(2)O(3) was suppressed by a dominant-negative effect of the transmembrane-deleted BNIP3 (BNIP3 Delta TM), autophagic cell death was inhibited. In contrast, BNIP3 transfection augmented As(2)O(3)-induced autophagic cell death. These results suggest that BNIP3 plays a central role in As(2)O(3)-induced autophagic cell death in malignant glioma cells. This study adds a new concept to characterize the pathways by which As(2)O(3) acts to induce autophagic cell death in malignant glioma cells.
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PMID:Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3. 1559 27

Arsenic trioxide (ATO) has been established to be an effective agent for treating newly diagnosed and relapsed acute promyelocytic leukemia (APL) patients. Laboratory data suggest that ATO induces apoptosis of hematopoietic or several solid tumor cells. However, to date, its effect on lung carcinoma has not been fully explored. In the present study, we investigated the effect of ATO on human lung carcinoma PG cells in vitro. We found ATO significantly inhibited the proliferation of PG cells in a dose- and time-dependent manner. ATO-induced apoptosis of PG cells was confirmed by the observance of typical morphological changes and detected by the analysis of flow cytometry (FCM). ATO significantly inhibited Bcl-2 and Pgp expression of PG cells by SABC immunohistochemistry and FCM analysis. In conclusion, our findings indicated that ATO induced apoptosis of PG cells and down-regulation of Bcl-2 and Pgp expressions, and these data might provide some theoretical basis for its clinical use in treating lung carcinoma.
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PMID:Effect of arsenic trioxide (ATO) on human lung carcinoma PG cell line: ATO induced apoptosis of PG cells and decreased expression of Bcl-2, Pgp. 1584 63

Arsenic trioxide (As2O3, arsenite) efficiently kills cells from various hematologic malignancies and has successfully been employed especially for the treatment of acute promyelocytic leukemia. There and in lymphoid cells, we demonstrated that As2O3 induces cell death in a caspase-2- and -9-independent fashion. Here, we address a potential role of death receptor signaling through the FADD/caspase-8 death-inducing signaling complex in As2O3-induced cell death. In detail, we demonstrate that As2O3 induces cell death independently of caspase-8 or FADD and cannot be blocked by disruption of CD95/Fas receptor ligand interaction. Unlike in death receptor ligation-induced apoptosis, As2O3-induced cell death was not blocked by the broad-spectrum caspase inhibitor z-VAD-fmk or the caspase-8-specific inhibitor z-IETD-fmk. Nevertheless, As2O3-induced cell death occurred in a regulated manner and was abrogated upon Bcl-2 overexpression. In contrast, As2O3-induced cell demise was neither blocked by the caspase-9 inhibitor z-LEHD-fmk nor substantially inhibited through the expression of a dominant negative caspase-9 mutant. Altogether our data demonstrate that As2O3-induced cell death occurs independently of the extrinsic death receptor pathway of apoptosis. Cell death proceeds entirely via an intrinsic, Bcl-2-controlled mitochondrial pathway that does, however, not rely on caspase-9.
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PMID:Arsenic trioxide induces regulated, death receptor-independent cell death through a Bcl-2-controlled pathway. 1600 34

Arsenic trioxide (ATO) induces apoptosis in a range of solid tumors and leukemia cells, and has been clinically applied for the treatment of acute promyelocytic leukemia with confirmed efficacy. Acute megakaryocytic leukemia (AMKL) is an aggressive malignancy with poor prognosis, if bone marrow transplantation is not possible. In this study, we applied flow cytometry, Western blot analysis and microarray techniques to investigate the effects of ATO on apoptosis and the cell division cycle of AMKL cell lines CHRF-288-11 and MEG-01. Our data demonstrated that ATO is a potent agent against AMKL as indicated by apoptotic markers, Annexin V and caspase-3. ATO activated the intrinsic (mitochondrial) pathway of apoptosis, which involved disrupting mitochondrial membrane potential, increased Bax/Bcl-2 ratio and caspase-9 activation, as well as the extrinsic (death receptor) pathway mediated by Fas and caspase-8 activation. We provided the first evidence that ATO stimulated expressions of CD137 mRNA and protein, which might be relevant to the extrinsic mechanism. ATO induced delays of cell cycle progression at S phase and arrest at G2/M phase of AMKL cells, but caspase-3 expression appeared not to be phase-specific. The multiple-signaling mechanism of ATO warrants it a potential agent to incorporate in the treatment regimen of AMKL.
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PMID:Arsenic trioxide mediates intrinsic and extrinsic pathways of apoptosis and cell cycle arrest in acute megakaryocytic leukemia. 1601 Apr 37

Arsenic trioxide has recently been shown to inhibit growth and induce apoptosis in a variety of hematologic malignancies, but very little is known about its effects on solid tumors and especially on neuroblastoma cells that have self-differentiating characteristics. To demonstrate the growth inhibition induced in neuroblastoma cells (the SH-SY5Y and SK-N-AS cell line) and acute promyelocytic leukemia cells (HL-60) by arsenic trioxide (As2O3), the viable cell numbers were counted after trypan blue staining. Apoptosis was assessed by the cell morphology, by flow cytometry with annexin-V staining, and by Western blot analysis for the apoptosis-related proteins (bcl-2 and PARP). To decide the dose for the clinical application of As2O3, normal peripheral blood lymphocytes were also examined. The growth and survival of the SH-SY5Y and SK-N-AS cells were markedly inhibited by As2O3 treatment at a 3 microM concentration before the changes of the normal lymphocytes were observed. The apoptotic cells showed a shrunken cell nucleus, and an increase in the number and balloon-like swelling of the mitochondria at 72 h after the As2O3 was added. Apoptosis of the annexin-V-positive cell proportion in the neuroblastoma cell lines was increased with increasing the exposure time and the concentration of As2O3, just like the HL-60 cells. Bcl-2 downregulation and PARP degradation were also noted all the cell lines, but these changes were not statistically significant among the 3 cell lines. Taken together, these results indicate that As2O3 is an excellent candidate as a therapeutic agent for the treatment of neuroblastoma.
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PMID:Morphological and biochemical changes induced by arsenic trioxide in neuroblastoma cell lines. 1616 54

Arsenic trioxide (ATO) is a novel agent for acute promylocytic leukemia (APL). Studies performed in vitro have demonstrated that ATO also induces cell-cycle arrest and apoptosis in multiple cancers, including non-APL acute myeloid leukemia (AML). To explore the potential use of ATO on non-APL AML, we treated the leukemic cells in vivo using a NOD/SCID animal model. Mice harboring HL-60 or NB-4 leukemia or primary AML-M2 cells were treated daily with 5 mug/g ATO intraperitoneally for a maximum of 6 weeks. Although ATO initially appeared to be effective on HL-60 cells, it failed to decrease the leukemic cells in bone marrow (BM) after the extended treatment (52.2 +/- 10.7% vs. 62.2 +/- 2.6% in the controls; P = 0.51); whereas the same treatment to NB-4 leukemic mice significantly decreased the percentage of leukemic cells in BM. ATO also failed to eradicate the primary AML cells in vivo. The reason for the treatment failure was that HL-60 cells quickly developed resistance in vivo. The drug resistance could be partly attributable to the increase of cellular glutathione as a result of compensatory response to ATO treatment because depletion of glutathione with buthionine sulfoximine reversed the drug resistance in vitro. Meanwhile, BM stromal cells also contributed to the drug resistance. Leukemic cells grown on an adherent layer of MS-5 stromal cells in the presence of ATO were more proliferative and less apoptotic and had increased expression cyclin D1, Bcl-xL and Bcl-2 and decreased expression of p21, likely protecting the leukemic cells from ATO cytotoxicity. Therefore, our study suggests that strategies to inhibit the compensatory increase of glutathione and block the interaction between leukemic cells and BM stromal cells should be employed before applying ATO to non-APL hematologic malignancies.
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PMID:Increased cellular glutathione and protection by bone marrow stromal cells account for the resistance of non-acute promylocytic leukemia acute myeloid leukemia cells to arsenic trioxide in vivo. 1639 76


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