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 (As2O3) has been demonstrated to be effective for the treatment of acute promyelocytic leukemia (APL) and to inhibit proliferation and produce apoptosis in the APL cell line NB4. To determine if As2O3 might be useful for the treatment of other lineages, we investigated the effects of As2O3 on viability, proliferation, and induction of apoptosis in the megakaryocytic leukemia cell lines HEL, Meg-01, UT7, and M07e. Our results showed that As2O3, at concentrations of 0.1-2.0 microM, causes a dose- and time-dependent inhibition of survival and growth in all four megakaryocytic leukemia cell lines studied. In contrast, As2O3 at similar concentrations had no effects on either viability or growth of the nonmegakaryocytic leukemia cell line HL60 and two human breast cancer cell lines, ZR75 and MCF7. In situ end-labeling of DNA fragments (TUNEL assay) indicated that As2O3, at concentrations of 0.5-2 microM, could significantly induce apoptosis in the aforementioned four megakaryocytic leukemia cell lines, but not in the nonmegakaryocytic HL60, ZR75, and MCF7 cell lines. These results were confirmed using conventional morphologic assessment and the DNA ladder assay. Induction of apoptosis in arsenic-treated Meg-01 and UT7 cells was accompanied by a dose-response decrease of Bcl-2 protein, whereas As2O3 had no effect on this measurement in HL60, ZR75, and MCF7 cell lines. Pertinently, these concentrations of As2O3 produced identical changes in the characteristics of the APL cell line NB4. Collectively, these data demonstrate that As2O3 can selectively inhibit growth and induce apoptosis in megakaryocytic leukemia cell lines. The use of As2O3 for the treatment of malignant megakaryocytic disorders should be considered.
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PMID:Effect of arsenic trioxide on viability, proliferation, and apoptosis in human megakaryocytic leukemia cell lines. 1034 Apr

Arsenic trioxide (As2O3) has been demonstrated to be effective for the treatment of acute promyelocytic leukemia (APL) and to inhibit proliferation and produce apoptosis in the APL cell line NB4. The effect of this newly utilized chemotherapeutic agent on other lineages is currently under study to evaluate its efficacy for the treatment of other human malignancies and myeloproliferative syndromes. A recent study described the effects of As2O3 upon viability, proliferation, and induction of apoptosis in four different megakaryocytic leukemia cell lines. At pharmacological concentrations (0.5-2 microM) As2O3 selectively inhibits growth and causes apoptosis in the megakaryocytic leukemia cell lines HEL, Meg-01, UT7 and M07e. Pertinently, these concentrations of As2O3 resulted in identical changes in the characteristics of the APL cell line NB4, suggesting that As2O3 could produce its effects in both cellular lineages via a common mechanism of action. Various mechanisms have been proposed for the As2O3-induced changes in NB4 (including modulation of promyelocytic leukemia proteins (PML) and Bcl-2, modification of the glutathione redox system, caspase activation, and cell cycle arrest) and are currently under investigation in the megakaryocytic leukemia cell lines. Recent preliminary results indicate that As2O3 downregulates Bcl-2 expression and induces cell cycle arrest in megakaryocytic cell lines. The use of As2O3 for the treatment of malignant megakaryocytic disorders also has been considered. The in vitro effects of As2O3 on a chronic megakaryocytic proliferative disorder. i.e., Essential Thrombocythemia (ET), have been analyzed and megakaryocyte progenitors have shown an unexpectedly higher resistance to As2O3, in comparison to normal megakaryocyte colony-forming cells. The effects of As2O3 on ET and other megakaryocytic disorders need to be fully examined, in order to determine the clinical efficacy of As2O3 in the treatment of syndromes affecting the megakaryocytic lineage.
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PMID:The effects of arsenic trioxide (As2O3) on human megakaryocytic leukemia cell lines. With a comparison of its effects on other cell lineages. 1081 58

Bcl-2 is an integral intracellular membrane protein that can protect cells from apoptosis induced by multiple insults in a variety of cell types. During apoptosis, Bcl-2 was cleaved into a shortened fragment (Bcl-2/Delta34) by a caspase-3-like protease in human Mo7e megakaryocytic leukemia cells deprived of exogenous rhGM-CSF. Results from cell fractionation and immunoblot analyses indicated that both Bcl-2 and Bcl-2/Delta34 were located exclusively on the mitochondria of Mo7e cells. Treatment of isolated mitochondria with recombinant caspase-3 induced the same cleavage of Bcl-2 in vitro and caused the release of cytochrome c from the mitochondria into the supernatant. The antiapoptotic effect of Bcl-2/Delta34 was investigated using an in vitro protein translation approach. Both Bcl-2/Delta34 and Bax proteins generated in wheat germ extract were readily relocated to the mitochondria isolated from control Mo7e cells. Insertion of Bax, but not Bcl-2/Delta34, into mitochondria triggered a rapid release of cytochrome c from the mitochondria. Coimmunoprecipitation studies showed that, unlike Bcl-2, the cleaved Bcl-2 fragment was no longer functional for dimerization with either Bcl-2 or Bax. Taken together, these findings showed that the integrity of Bcl-2 is necessary for its function of heterodimerization with Bax, which appears to be one of the mechanisms of antiapoptotic effect of Bcl-2.
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PMID:Apoptosis of Mo7e leukemia cells is associated with the cleavage of Bcl-2 into a shortened fragment that is not functional for heterodimerization with Bcl-2 and Bax. 1108 88

The growth of M-07e human megakaryocytic leukemia cells is strictly dependent on GM-CSF. In M-07e cells, the GM-CSF receptor (GM-CSF R) is composed of two subunits: a low affinity alpha subunit and a phosphorylated beta subunit, which is constitutively linked to lyn(53/56) protein tyrosine kinase. In this study, The role of lyn kinase in regulating TGF-beta 1-induced apoptosis in M-07e cells was examined. The removal of rhGM-CSF from the culture medium resulted in down-regulation of lyn kinase activity, followed by growth inhibition and programmed cell death. Apoptosis of M-07e cells was accompanied with a massive cleavage of Bcl-2 and Bax proteins into shortened fragments with molecular mass of 22 kD and 18 kD, respectively. Using specific inhibitors, the cleavage of Bcl-2, but not Bax, was found to be processed through activated caspase-3 (CPP32), which is abundantly expressed in M-07e cells. TGF-beta 1 inhibited rhGM-CSF-stimulated cell growth and promoted apoptosis in M-07e cells with a pattern identical to that induced by rhGM-CSF depletion, which included massive cleavage of both Bcl-2 and Bax proteins and inactivation of lyn kinase activity. TGF-beta 1 did not affect the levels of lyn protein or the beta-subunit, neither did it block the interaction between these two components. Also, TGF-beta 1 treatment did not diminish the expression of the alpha subunit in M-07e cells. Our results showed that TGF-beta 1 inhibits cell proliferation and promotes apoptosis in M-07e cells by inactivating the GM-CSF R-associated lyn kinase activity. Further, This study showed that Bcl-2 cleavage by activated CPP32 is a naturally occurring event associated with apoptosis, which is under the regulation of lyn kinase activation.
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PMID:Cleavage of Bcl-2 Protein by Activated Caspase-3 Is Associated with Inactivation of Lyn(p53/56) Kinase Activity in Human M-07e Leukemic Cells during Apoptosis. 1257 76

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