Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism of the cytotoxic effect of boswellic acid acetate, a 1:1 mixture of alpha-boswellic acid acetate and beta-boswellic acid acetate, isolated from Boswellia carterri Birdw on myeloid leukemia cells was investigated in six human myeloid leukemia cell lines (NB4, SKNO-1, K562, U937, ML-1, and HL-60 cells). Morphologic and DNA fragmentation assays indicated that the cytotoxic effect of boswellic acid acetate was mediated by induction of apoptosis. More than 50% of the cells underwent apoptosis after treatment with 20 mug/mL boswellic acid for 24 hours. This apoptotic process was p53 independent. The levels of apoptosis-related proteins Bcl-2, Bax, and Bcl-XL were not modulated by boswellic acid acetate. Boswellic acid acetate induced Bid cleavage and decreased mitochondrial membrane potential without production of hydrogen peroxide. A general caspase inhibitor (Z-VAD-FMK) and a specific caspase-8 inhibitor II (Z-IETD-FMK) blocked boswellic acid acetate-induced apoptosis. The mRNAs of death receptors 4 and 5 (DR4 and DR5) were induced in leukemia cells undergoing apoptosis after boswellic acid acetate treatment. These data taken together suggest that boswellic acid acetate induces myeloid leukemia cell apoptosis through activation of caspase-8 by induced expression of DR4 and DR5, and that the activated caspase-8 either directly activates caspase-3 by cleavage or indirectly by cleaving Bid, which in turn decreases mitochondria membrane potential.
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PMID:Boswellic acid acetate induces apoptosis through caspase-mediated pathways in myeloid leukemia cells. 1576 47

Dimethyl sulfoxide (DMSO) is a widely used prototypical chemical inducer of cell differentiation. In the present study, the effects of DMSO on susceptibility of human myeloid leukemia U937 cells towards ligation of distinct death receptors (DRs) were investigated. DMSO sensitized cells towards induction of apoptosis by anti-Fas antibody, tumour necrosis factor-alpha or Apo2 ligand/TNF-related apoptosis-inducing ligand (TRAIL). Apart from increasing Fas levels, DMSO did not affect expression of proteins in death signal transduction, such as Bcl-2 family proteins, FADD, caspase-3 and -8, the inhibitor of apoptosis proteins (IAPs) or cFLIP(L). However, DMSO significantly potentiated mitochondrial membrane depolarization, suggesting that this mechanism might be involved in sensitisation of myeloid cells to DR-mediated apoptosis.
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PMID:Dimethyl sulfoxide potentiates death receptor-mediated apoptosis in the human myeloid leukemia U937 cell line through enhancement of mitochondrial membrane depolarization. 1599 40

Melatonin is an indoleamine that is synthesized in the pineal gland and has an extensive repertoire of biological activities. In the present study, we found that melatonin reduced the growth of the human myeloid leukemia cells HL-60, inhibiting progression from G(1) to S phase of the cell cycle and increasing apoptotic cell death. Furthermore, melatonin treatment elevated cytochrome c release from mitochondria and augmented caspase-3 and caspase-9 activities. Upregulation of Bax and downregulation of Bcl-2 was also observed upon melatonin treatment. The effects of melatonin were found not to be mediated by membrane receptors for the indoleamine. Together, our results suggest that melatonin reduces the viability of HL-60 cells via induction of apoptosis primarily through regulation of Bax/Bcl-2 expression.
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PMID:Inhibition of proliferation and induction of apoptosis by melatonin in human myeloid HL-60 cells. 1728 44

Treatment with the anti-leukemic drug arsenic trioxide (As(2)O(3), 1-4 microM) sensitizes U937 promonocytes and other human myeloid leukemia cell lines (HL60, NB4) to apoptosis induction by TNFalpha. As(2)O(3) plus TNFalpha increases TNF receptor type 1 (TNF-R1) expression, decreases c-FLIP(L) expression, and causes caspase-8 and Bid activation, and apoptosis is reduced by anti-TNF-R1 neutralizing antibody and caspase-8 inhibitor. The treatment also causes Bax translocation to mitochondria, cytochrome c and Omi/HtrA2 release from mitochondria, XIAP down-regulation, and caspase-9 and caspase-3 activation. Bcl-2 over-expression inhibits cytochrome c release and apoptosis, and also prevents c-FLIP(L) down-regulation and caspase-8 activation, but not TNF-R1 over-expression. As(2)O(3) does not affect Akt phosphorylation/activation or intracellular GSH content, nor prevents the TNFalpha-provoked stimulation of p65-NF-kappaB translocation to the nucleus and the increase in NF-kappaB binding activity. Treatments with TNFalpha alone or with As(2)O(3) plus TNFalpha cause TNF-R1-mediated p38-MAPK phosphorylation/activation. P38-MAPK-specific inhibitors attenuate the As(2)O(3) plus TNFalpha-provoked activation of caspase-8/Bid, Bax translocation, cytochrome c release, and apoptosis induction. In conclusion, the sensitization by As(2)O(3) to TNFalpha-induced apoptosis in promonocytic leukemia cells is an Akt/NF-kappaB-independent, p38-MAPK-regulated process, which involves the interplay of both the receptor-mediated and mitochondrial executioner pathways.
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PMID:Arsenic trioxide sensitizes promonocytic leukemia cells to TNFalpha-induced apoptosis via p38-MAPK-regulated activation of both receptor-mediated and mitochondrial pathways. 1767 11

Caffeic acid phenyl ester (CAPE), a biologically active ingredient of propolis, has several interesting biological properties including antioxidant, anti-inflammatory, antiviral, immunostimulatory, anti-angiogenic, anti-invasive, anti-metastatic and carcinostatic activities. Recently, several groups have reported that CAPE is cytotoxic to tumor cells but not to normal cells. In this study, we investigated the mechanism of CAPE-induced apoptosis in human myeloid leukemia U937 cells. Treatment of U937 cells with CAPE decreased cell viability in a dose-dependent and time-dependent manner. DNA fragmentation assay revealed the typical ladder profile of oligonucleosomal fragments in CAPE-treated U937 cells. In addition, as evidenced by the nuclear DAPI staining experiment, we observed that the nuclear condensation, a typical phenotype of apoptosis, was found in U937 cells treated with 5 microg/ml of CAPE. Therefore, it was suggested that CAPE is a potent agent inducing apoptosis in U937 cells. Apoptotic action of the CAPE was accompanied by release of cytochrome C, reduction of Bcl-2 expression, increase of Bax expression, activation/cleavage of caspase-3 and activation/cleavage of PARP in U937 cells, but not by Fas protein, an initial mediator in the death signaling, or by phospho-eIF2 alpha and CHOP, crucial mediators in ER-mediated apoptosis. From the results, it was concluded that CAPE induces the mitochondria-mediated apoptosis but not death receptors- or ER-mediated apoptosis in U937 cells.
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PMID:Caffeic acid phenethyl ester induces mitochondria-mediated apoptosis in human myeloid leukemia U937 cells. 1806 Apr 75

1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3] is capable of inhibiting the proliferation of acute myelogenous leukemia (AML). However, toxicity of hypercalcemia has limited the use of 1,25(OH)2D3 in clinical trials. We have evaluated 11 synthesized vitamin D3 analogs for their ability to inhibit clonal growth of HL-60 myeloid leukemic cells. Among the 11 vitamin D3 analogs, HY-11 (code name) showed the most potent antileukemic activity with 2.5x10(-6) M of IC50, however, it did not affect the cellular growth of normal peripheral blood mononuclear cells until 10(-6) M. Flow cytometric analysis indicated that HY-11 induced the G1 arrest in a dose-dependent manner, which was mediated via inactivation of CDK4 and CDK6 in association with up-regulation of CDKI (cyclin-dependent kinase inhibitor), p27 and Rb protein. Induction of apoptosis was mediated via caspase-3 pathway in HY-11-treated HL-60. In addition, HY-11 enhanced the expression of TGF-beta1, TGF-beta receptor type I and II and vitamin D3 receptor (VDR). VDR expression was increased by TGF-beta1, suggesting that TGF-beta1 might be involved in the antiproliferative effect of HY-11 on HL-60 cells by autocrine and paracrine regulation. Serum calcium levels were within normal limit when HY-11 was given intraperitoneally (i.p.) every other day for 5 weeks to BALB/c mice at the doses of 10(-7), 10(-6)and 10(-5) M. HY-11 inhibited the growth of WEHI-3BD+ mouse leukemic cells in vitro, and syngeneic BALB/c mice that received WEHI-3BD+ mouse leukemic cells and HY-11 had a significantly longer survival without producing hypercalcemia compared to control group. In summary, HY-11 is a vitamin D3 analog that inhibited the proliferation of human AML cell line, HL-60, through induction of cell cycle arrest, triggering apoptosis as well as modulation of TGF-beta1 and its receptors. In particular, HY-11 significantly increased the survival of mice that had myeloid leukemia without producing hypercalcemia.
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PMID:Antileukemic effect of a synthetic vitamin D3 analog, HY-11, with low potential to cause hypercalcemia. 1820 61

The cytotoxicity of beta-cyclodextrin benzaldehyde inclusion compound (CDBA) against human normal and cancer cell lines was investigated. CDBA showed slightly higher cytotoxicity against human tumor cell lines, as compared to normal cells, with a tumor-specificity index of 2.2. Human myelogenous leukemia cell lines (HL-60, ML-1, KG-1) were the most sensitive to CDBA, followed by human oral squamous cell carcinoma (HSC-2, HSC-3, HSC-4) and human glioblastoma (T98G, U87MG). Human normal cells (gingival fibroblasts, pulp cells, periodontal ligament fibroblasts) were the most resistant. CDBA induced internucleosomal DNA fragmentation in HL-60 cells and caspase-3, -8, -9 activation, but to a much lesser extent than that attained by UV irradiation or actinomycin D. On the other hand, CDBA did not induce DNA fragmentation, nor caspase activation in HSC-2, HSC-4 or T98G cells. Electron microscopy demonstrated that CDBA induced the destruction of mitochondrial structure and digestion of broken organelles by secondary lysosomes in all of these cells. CDBA also increased the number of acidic organelles as judged by acridine orange staining. The present study suggests that CDBA induces autophagic cell death in cancer cell lines.
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PMID:Tumor-specific cytotoxicity and type of cell death induced by beta-cyclodextrin benzaldehyde inclusion compound. 1838 50

Human intestinal infections by Shiga toxin (Stx)-producing Escherichia coli cause hemorrhagic colitis and hemolytic uremic syndrome (HUS), which represents the main cause of acute renal failure in early childhood. In HUS, Stx released in the gut enter the bloodstream and are targeted to renal endothelium. The mechanism of toxin delivery is still a matter of debate, although the role of polymorphonuclear leukocytes (PMN) as a Stx carrier has been indicated. The aim of this paper was to better define the interactions between Stx and human PMN. Direct and indirect flow cytometric analysis and binding experiments with radiolabeled toxins demonstrated that Stx bind to the surface of human mature PMN but not to immature PMN from G-CSF-treated donors. The use of the human myeloid leukemia cell (HL-60) model for inducible cell differentiation confirmed that the toxin binding occurs only after granulocytic differentiation. Stx binding caused a delay of the spontaneous apoptosis of PMN, as shown by the delayed appearance of apoptotic nuclei and activation of caspase 3 and by the higher number of cells negative to the annexin V-binding assay after 48 h. Moreover, flow cytometric analysis of mixed Stx-positive and Stx-negative PMN populations showed that the toxins were transferred from positive to negative PMN. The delayed, spontaneous apoptosis and the passage of the toxic ligand from older PMN to new, mature cells entering the circulation from the bone marrow may explain the previously reported persistence of Stx in the blood of children with HUS.
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PMID:Interactions between Shiga toxins and human polymorphonuclear leukocytes. 1862 12

Through cytotoxicity screening with naphthoquinone derivatives, a novel compound 6-(1-oxoallkyl)-5,8-dimethoxy-1,4-naphthoquinone-S17 (DMNQ-S17) showed its potency against human myeloid leukemia U937 cells. Thus, to elucidate the apoptotic mechanism of DMNQ-S17, this study was performed in myeloid leukemia U937 cells by 2,3-bis [2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide (XTT) assay, eletrophoretic mobility shift assay (EMSA), terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay, 4',6-diamidino-2-phenylindole (DAPI) staining, and Western blotting. In the present study, DMNQ-S17 inhibited constitutive NF kappaB activation and its transcriptional activity in U937 cells. In addition, DMNQ-S17 induced apoptotic features such as apoptotic bodies, cell shrinkage and chromatin condensation in U937 cells. Consistently, flow cytometric analysis showed that DMNQ-S17 increased sub-G1 portion and TUNEL positive cells in a concentration-dependent manner. Furthermore, DMNQ-S17 effectively attenuated mitochondrial membrane potential, released cytochrome C, activated caspase-3 expression, and cleaved poly (ADP-ribose) polymerase (PARP). Reversely, caspase-3 and -9 inhibitors also blocked the DMNQ-S17 induced caspase-3 activation and PARP cleavage in U937 cells. Taken together, these findings suggest that DMNQ-S17 can be a potent anticancer candidate for myeloid leukemias by the suppression of NF-kappaB activation leading to the activation of caspase-3 in human myeloid leukemia U937 cells.
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PMID:DMNQ-S17 inhibits constitutive NF-kappaB activation leading to induction of apoptosis through the activation of caspase-3 in human myeloid leukemia U937 cells. 1871 43

Withaferin A (WA) is present abundantly in Withania somnifera, a well-known Indian medicinal plant. Here we demonstrate how WA exhibits a strong growth-inhibitory effect on several human leukemic cell lines and on primary cells from patients with lymphoblastic and myeloid leukemia in a dose-dependent manner, showing no toxicity on normal human lymphocytes and primitive hematopoietic progenitor cells. WA-mediated decrease in cell viability was observed through apoptosis as demonstrated by externalization of phosphatidylserine, a time-dependent increase in Bax/Bcl-2 ratio; loss of mitochondrial transmembrane potential, cytochrome c release, caspases 9 and 3 activation; and accumulation of cells in sub-G0 region based on DNA fragmentation. A search for the downstream pathway further reveals that WA-induced apoptosis was mediated by an increase in phosphorylated p38MAPK expression, which further activated downstream signaling by phosphorylating ATF-2 and HSP27 in leukemic cells. The RNA interference of p38MAPK protected these cells from WA-induced apoptosis. The RNAi knockdown of p38MAPK inhibited active phosphorylation of p38MAPK, Bax expression, activation of caspase 3 and increase in Annexin V positivity. Altogether, these findings suggest that p38MAPK in leukemic cells promotes WA-induced apoptosis. WA caused increased levels of Bax in response to MAPK signaling, which resulted in the initiation of mitochondrial death cascade, and therefore it holds promise as a new, alternative, inexpensive chemotherapeutic agent for the treatment of patients with leukemia of both lymphoid and myeloid origin.
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PMID:Withaferin A induces apoptosis by activating p38 mitogen-activated protein kinase signaling cascade in leukemic cells of lymphoid and myeloid origin through mitochondrial death cascade. 1898 75


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