Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Giant proerythroblasts are hallmarks of human parvovirus B19 infection. We attempted to characterize these cells in 5 patients with parvovirus B19-induced pure red cell aplasia using immunostaining of paraffin-embedded bone marrow sections with antibodies against erythroid-lineage-specific proteins, viral capsid antigen VP-1, and apoptosis- and cell-cycle-related proteins. Giant proerythroblasts are immunohistochemically consistent with early erythroid precursors of cells in the differentiation stage of CD34-, cytoplasmic spectrin+, glycophorin A-, and band-3-. VP-1 was expressed in the nucleus and cytoplasm of small- to medium-sized spectrin+ erythroid cells but not in giant proerythroblasts. The giant proerythroblasts displayed nuclear staining for p53 (41%+/-16%) and Ki-67 antigen (100%+/-0%) and cytoplasmic staining for Bax (65%+/-11%) and procaspase-3 (78%+/-10%), whereas they were not stained for p21Wafl/Cip1, active form of caspase-3, or terminal deoxynucleotidyltransferase-mediated deoxyuridine nick-end labeling (TUNEL). Antiapoptotic proteins, Bcl-2 and Mcl-1, were not expressed in the giant cells, and Bcl-x was infrequently expressed in these cells (11%+/-4%). These immunohistochemical findings suggest that giant proerythroblasts are proliferating erythroid precursors with accumulation of nonfunctional p53.
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PMID:Expression of p53 and Ki-67 antigen in bone marrow giant proerythroblasts associated with human parvovirus B19 infection. 1159 14

It has been shown that the novel synthetic triterpenoid CDDO inhibits proliferation and induces differentiation and apoptosis in myeloid leukemia cells. In the current study the effects of the C-28 methyl ester of CDDO, CDDO-Me, were analyzed on cell growth and apoptosis of leukemic cell lines and primary acute myelogenous leukemia (AML). CDDO-Me decreased the viability of leukemic cell lines, including multidrug resistant (MDR)-1-overexpressing, p53(null) HL-60-Dox and of primary AML cells, and it was 3- to 5-fold more active than CDDO. CDDO-Me induced a loss of mitochondrial membrane potential, induction of caspase-3 cleavage, increase in annexin V binding and DNA fragmentation, suggesting the induction of apoptosis. CDDO-Me induced pro-apoptotic Bax protein that preceded caspase activation. Furthermore, CDDO-Me inhibited the activation of ERK1/2, as determined by the inhibition of mitochondrial ERK1/2 phosphorylation, and it blocked Bcl-2 phosphorylation, rendering Bcl-2 less anti-apoptotic. CDDO-Me induced granulo-monocytic differentiation in HL-60 cells and monocytic differentiation in primary cells. Of significance, colony formation of AML progenitors was significantly inhibited in a dose-dependent fashion, whereas normal CD34(+) progenitor cells were less affected. Combinations with ATRA or the RXR-specific ligand LG100268 enhanced the effects of CDDO-Me on cell viability and terminal differentiation of myeloid leukemic cell lines. In conclusion, CDDO-Me is an MDR-1- and a p53-independent compound that exerts strong antiproliferative, apoptotic, and differentiating effects in myeloid leukemic cell lines and in primary AML samples when given in submicromolar concentrations. Differential effects of CDDO-Me on leukemic and normal progenitor cells suggest that CDDO-Me has potential as a novel compound in the treatment of hematologic malignancies.
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PMID:Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia. 1175 88

Platelets are formed from mature megakaryocytes (MKs) and arise from the development of long and thin cytoplasmic extensions called proplatelets. After platelet release, the senescent MKs (nucleus surrounded by some cytoplasm) undergo cell death by apoptosis. To explore the precise role of apoptosis in proplatelet formation, we grew human MKs from CD34(+) cells and assessed the possible role of caspases. Proteolytic maturation of procaspase-3 and procaspase-9 was detected by immunoblots in maturing MKs as well as in proplatelet-bearing MKs and senescent MKs. Cleavage of caspase substrates such as gelsolin or poly adenosine diphosphate (ADP)-ribose polymerase (PARP) was also detected. Interestingly, activated forms of caspase-3 were detected in maturing MKs, before proplatelet formation, with a punctuate cytoplasmic distribution, whereas a diffuse staining pattern was seen in senescent and apoptotic MKs. This localized activation of caspase-3 was associated with a mitochondrial membrane permeabilization as assessed by the release of cytochrome c, suggesting an activation of the intrinsic pathway. Moreover, these MKs with localized activated caspase-3 had no detectable DNA fragmentation. In contrast, when apoptosis was induced by staurosporine, diffuse caspase activation was seen; these MKs had signs of DNA fragmentation, and no proplatelet formation occurred. The pan-caspase inhibitor z-VAD.fmk as well as more specific inhibitors of caspase-3 and caspase-9 blocked proplatelet formation, whereas an inhibitor of calpeptin had no effect. Overexpression of Bcl-2 also inhibited proplatelet formation in maturing MKs. Thus, localized caspase activation is causal to proplatelet formation. We conclude that proplatelet formation is regulated by a caspase activation limited to only some cellular compartments.
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PMID:Platelet formation is the consequence of caspase activation within megakaryocytes. 1214 86

Increased apoptosis of hematopoietic progenitor cells has been implicated in the pathophysiology of cytopenias associated with myelodysplastic syndromes (MDSs), and inhibition by immunosuppression may account for the success of this treatment in some patients. We examined bone marrow and peripheral blood of 25 patients with chromosomal abnormalities associated with MDS (monosomy 7, trisomy 8, and 5q-) for evidence of apoptosis. When fresh bone marrow was examined, the number of apoptotic and Fas-expressing CD34 cells was increased in patients with trisomy 8, but decreased in monosomy 7, as compared with healthy control donor marrow. Fas expression was increased in the trisomy 8 cells and decreased in the monosomy 7 cells when compared with normal cells from the same patient. Trisomy 8 cells were more likely to express activated caspase-3 than were normal cells. For bone marrow cells cultured with Fas agonist or Fas antagonist, the percentage of cells with trisomy 8 was significantly decreased in most cases after Fas receptor triggering and increased by Fas ligand (Fas-L) antagonist (P < 0.01), suggesting increased Fas susceptibility of cells with trisomy 8. No such changes were seen in cultures of cells with 5q- or monosomy 7. Fas antagonist facilitated the expansion of cells with trisomy 8 only. Cells with trisomy 8 appear to be more susceptible to Fas-mediated apoptosis. Clinical data demonstrating the responsiveness of some patients with trisomy 8 to anti-thymocyte globulin (ATG) and cyclosporine (CsA) would favor an active role of the immune system in this syndrome.
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PMID:Fas-mediated apoptosis is important in regulating cell replication and death in trisomy 8 hematopoietic cells but not in cells with other cytogenetic abnormalities. 1239 49

To evaluate expression of caspase-3 protein in CD34(+) cells from cord blood (CB) and its significance during culture in vitro with various growth factors, RT-PCR, Western blot and flow cytometry were used to determine cell proliferation, apoptosis and expression of caspase-3 in CD34(+) cells during culture in vitro. The results demonstrated that caspase-3 mRNA was constitutively expressed at a low level in freshly isolated CD34(+) cells. Expression of caspase-3 mRNA and protein was upregulated when these cells were expanded in suspension culture with growth factors for 3 days. However, only the 32 kD inactive caspase-3 proenzyme was detected in the freshly isolated CD34(+) cells and those cells after 3 days expansion with cytokines. Along with the culture time extension (7 days) in vitro, especially without early-effective cytokines SCF or FL existence, caspase-3 was activated and a cleavage 20 kD was detected. It is concluded that the caspase-3 is involved in apoptosis of primitive CD34(+) cells during expansion in vitro, and early-effective cytokines, SCF and FL, could conserve hematopoietic stem cells and suppress apoptosis.
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PMID:Expression of caspase-3 in CD34+ cord blood cells and its significance. 1251 33

The objective is to explore the effect and the mechanism of arsenic trioxide, As(2)O(3), on different cell lines of chronic myeloid leukemia (CML). Different concentrations of As(2)O(3) (0.2, 2 and 10 micro mol/L) were added to CML cell lines KU812 and MEG-01 and other leukemia cell lines U937 and PL21, the cell numbers were counted at different times, TUNEL and DNA ladder were assayed. Different antibodies, CD34, CD13, CD33, CD19, CD11b, CD14 and CD7, were added to detect the change of the molecules on cell surface, the change of bcr-abl by RT-PCR and the activity of caspase-3 were assayed. The results showed that different concentrations of As(2)O(3) had different effects on the survival of the 4 cell lines. After culture for 24 hours with As(2)O(3), there was no significant increase in CD11b in all the four cell lines. There were no changes of bcr-abl in the two CML cell lines treated and untreated with As(2)O(3) by RT-PCR. Activities of caspase-3 were all increased. It is concluded that As(2)O(3) can induce apoptosis in CML cell lines, the concentration to induce apoptosis is different, CML cell lines are more sensitive than the other 2 leukemia cell lines. As(2)O(3) induced apoptosis may have some relation with the activation of caspase-3.
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PMID:Effect of arsenic trioxide on different cell lines derived from chronic myeloid leukemia. 1251 39

There is increasing use of human umbilical cord blood (UCB) stem cells for unrelated donor transplantation. Successful engraftment depends in large measure on the dose and quality of cells in the UCB unit. In the present study, we attempted to identify a simple and rapid technique for assessing the quality and recovery of UCB cells following laboratory manipulation. Mononuclear cells (MNC) from fresh (<48 h old) and thawed UCB units were stained with 7-amino-actinomycin D (7-AAD), revealing 2-3% dead cells. The frequencies of apoptotic cells in fresh and thawed sample were similar. However, UCB held for 72 h showed higher levels of cell deterioration. Interestingly, staining with 7-AAD was more sensitive to cellular damage than was uptake of Trypan Blue. 7-AAD staining of MNC also correlated with retention of hematopoietic function (progenitor assays) such that 7-AAD staining frequencies <20% predicted maintenance of hematopoietic cells. Importantly, hematopoietic precursors were less susceptible to storage injury than were UCB MNC as a whole. MNC showed higher levels of 7-AAD staining and apoptosis than did CD34(+) cells. This observation was confirmed in studies of caspase-3 activation, where MNC consistently showed higher frequencies of activation than did CD34(+) cells, especially after overnight storage. Furthermore, antiapoptotic proteins Bcl-2 and Bcl-x were expressed more consistently in CD34(+) cells than in total MNC. In contrast, Bax levels increased with MNC apoptosis. In conclusion, the data suggest that 7-AAD staining of UCB MNC provides a rapid and simple technique for assessing the viability, recovery, and hematopoietic functionality of stored UCB.
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PMID:Assessment of cell viability and apoptosis in human umbilical cord blood following storage. 1266 42

To investigate the role and mechanism of apoptosis in cryoinjury of cord blood hematopoietic stem/progenitor cells, apoptosis of CD34(+) cells, mitochondrial membrane potential (MMP) and Fas antigen expression were detected by flow cytometry (FCM), the Bcl-2 protein expression was detected by immunohistochemistry, caspase-3 expression was determined by Western blot and caspase-3 activity analysis, colony-forming units (CFU) was performed by semi-solid methylcellulose culture. The results showed that when cells were store at -196 degrees C for 2 weeks or 4 weeks, apoptotic cells increased, gel electrophoresis displayed typical DNA ladder, and CFU decreased by 25.2% and 30.1%. The value of MMP reduced and expression of Bcl-2 protein was down-regulated during the freeze-thaw process, but the Fas antigen expression was not effected. However, only the 32 kD inactive caspase-3 proenzyme was detected in freshly isolated CD34(+) cells. After freeze-thaw, caspase-3 was activated and a cleavage of 20 kD protein was detected. Cryopreserved cells showed a 1.2-fold and 1.5-fold increase in caspase-3 activity, respectively. It is concluded that apoptosis plays an important role in cryoinjury of cord blood hematopoietic stem/progenitor cells, which triggers a mitochondrial apoptotic pathway that is caspase-dependent but does not require death receptors, where caspase-3 is the key effector.
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PMID:[Role of apoptosis in cryoinjury of cord blood hematopoietic stem/progenitor cells and its mechanism]. 1498 78

The reputation of garlic (Allium sativum) as an effective remedy for tumours extends back to the Egyptian Codex Ebers of 1550 b.c. Several garlic compounds including allicin and its corresponding sulfide inhibit the proliferation and induce apoptosis of several human non-leukaemia malignant cells including breast, bladder, colorectal, hepatic, prostate cancer, lymphoma and skin tumour cell lines. Ajoene (4,5,9-trithiadodeca-1,6,11-triene-9-oxide) is a garlic-derived compound produced most efficiently from pure allicin and has the advantage of a greater chemical stability than allicin. Several clinical trials and in vitro studies of ajoene have demonstrated its best-known anti-thrombosis, anti-microbial and cholesterol lowering activities. Recently, topic application of ajoene has produced significant clinical response in patients with skin basal cell carcinoma. Ajoene was shown to inhibit proliferation and induce apoptosis of several human leukaemia CD34-negative cells including HL-60, U937, HEL and OCIM-1. Also, ajoene induces 30% apoptosis in myeloblasts from chronic myeloid leukaemia patient in blast crisis. More significantly, ajoene profoundly enhanced the apoptotic effect of the two chemotherapeutic drugs: cytarabine and fludarabine in human CD34-positive resistant myeloid leukaemia cells through enhancing their bcl-2 inhibitory and caspase-3 activation activities. The two key anti-leukaemia biological actions of ajoene were the inhibition of proliferation and the induction of apoptosis. Studies have shown the anti-proliferation activity of ajoene to be associated with a block in the G2/M phase of cell cycle in human myeloid leukaemia cells. The apoptosis inducing activity of ajoene is via the mitochondria-dependent caspase cascade through a significant reduction of the anti-apoptotic bcl-2 that results in release of cytochrome c and the activation of caspase-3. Since acute myeloid leukaemia (AML) is a heterogeneous malignant disease in which disease progression at the level of CD34-positive cells has a major impact on resistance to chemotherapy and relapse and the inability to undergo apoptosis is a crucial mechanism of multi-drug resistance in AML patients. The recent findings of the potent enhancing activity of ajoene on chemotherapy-induced apoptosis in CD34-positive resistant human myeloid leukaemia cells suggest a novel promising role for the treatment of refractory and/or relapsed AML patients as well as elderly AML patients. Further studies are warranted to evaluate similar enhancing effect for ajoene in blast cells from AML patients in primary cultures before its introduction in pilot clinical study.
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PMID:Ajoene (natural garlic compound): a new anti-leukaemia agent for AML therapy. 1515 86

Imatinib (STI571, Gleevec) is a tailored drug for chronic myelogenous leukemia (CML), whereas arsenic compounds were used as ancient remedies for CML with certain efficacy. The aim of this study was to investigate the potential benefit of combination therapy with imatinib and arsenic sulfide (As(4)S(4)). Analysis of cell proliferation and clonogenic ability showed that As(4)S(4) and imatinib exerted synergistic effects on both K562 cells and fresh CML cells. The effective concentrations on fresh CML cells were pharmacokinetically available in vivo but had much less inhibitory effect on CD34(+) cells from the nonleukemic donors. Examination of cell cycles showed that As(4)S(4) induced G(2)/M arrest whereas imatinib induced G(1) arrest. Using a number of parameters such as morphology, annexin V/propidium iodide (PI), mitochondrial transmembrane potential, caspase-3 activity, and Fas/Fas-L, the synergistic effects were revealed on induction of cell apoptosis, largely through the mitochondrial pathway. The 2 drugs also exhibited a synergistic effect in targeting BCR-ABL protein. While As(4)S(4) triggered its degradation and imatinib inhibited its tyrosine kinase activity, combined use of the 2 led to lower protein/enzymatic activity levels of BCR-ABL. Our in vitro data thus strongly suggest a potential clinical application of imatinib and As(4)S(4) combination on CML.
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PMID:Combined effects of As4S4 and imatinib on chronic myeloid leukemia cells and BCR-ABL oncoprotein. 1533 52


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