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)

Annonaceous acetogenins have potent antitumor effect in vitro and in vivo. Squamocin is one of the annonaceous acetogenins and has been reported to have antiproliferative effect on cancer cells. Our results from this study showed that squamocin inhibited proliferation of HL-60 cells with IC50 value of 0.17 microg/ml and induced apoptosis of HL-60 cells. Investigation of the mechanism of squamocin-induced apoptosis revealed that treatment of HL-60 cells with squamocin resulted in extensive nuclear condensation. DNA fragmentation, cleavage of the death substrate poly (ADP-ribose) polymerase (PARP) and induction of caspase-3 activity. Pretreatment of HL-60 cells with caspase-3 specific inhibitor DEVD-CHO prevented squamocin-induced DNA fragmentation, PARP cleavage and cell death. The expression levels of protein bcl-2, bax have no change in response to squamocin treatment in HL-60 cells, whereas stress-activated protein kinase (SAPK/JNK) was activated after treatment with squamocin in HL-60 cells. These results suggest that apoptosis of HL-60 cells induced by squamocin requires caspase-3 activation and is related to SAPK activation.
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PMID:Involvement of caspase-3 activation in squamocin-induced apoptosis in leukemia cell line HL-60. 1188 4

Angiotensin II (ANG II) via AT(1) receptors induces apoptosis in cardiomyocytes in vitro. We tested the hypothesis that in vivo AT(1) receptor stimulation is accompanied by cardiac apoptosis and attempted to elucidate the molecular mechanisms involved in the death signaling pathway. Male Sprague-Dawley rats received ANG II (120 ng x kg(-1) x min(-1) sc) for 7 days with or without the AT(1) receptor antagonist losartan (10 mg x kg(-1) x day(-1) orally). Cardiac function was assessed by echocardiography. Apoptosis in the heart was detected and quantified by in situ TdT-mediated dUTP nick-end labeling (TUNEL) and radiolabeled DNA laddering. Expression of bax, bcl-2, caspase 3, and AT(1) and AT(2) receptors was examined by Western blot analysis. Activity of caspase 3 was also measured by a fluorometric immunosorbent enzyme assay. Tail cuff systolic blood pressure was elevated (P < 0.01, n = 6) in ANG II-infused rats (173 +/- 3 mmHg) versus controls (111 +/- 2 mmHg) and reduced by losartan (134 +/- 4 mmHg). Cardiac function was essentially unchanged in ANG II-infused rats. Increased internucleosomal DNA cleavage by TUNEL assay and radiolabeled DNA laddering showed results compatible with enhanced cardiomyocyte apoptosis in the hearts of ANG-II infused rats. The bax-to-bcl-2 ratio, expression of the active form of caspase 3 (17 kDa), and activity of caspase 3 in the hearts of the ANG II group increased more than twofold above controls. Protein expression of AT(1) and AT(2) receptors was significantly increased in ANG II-infused rats compared with control rats. Losartan-treated ANG II-infused rats exhibited normalized apoptosis, bax, caspase 3 activity, and AT(1) receptors. ANG II stimulation of AT(1) receptors in the heart in vivo is associated with an increased rate of apoptosis without major hemodynamic consequences. Bax and caspase 3 are involved in the apoptotic signaling pathway in this experimental paradigm.
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PMID:Effect of AT(1) receptor blockade on cardiac apoptosis in angiotensin II-induced hypertension. 1195 25

During the early stages of heart development, there are two main foci of cell death: outflow tract (OT) and atrioventricular (AV) endocardial cushions. These tissues contribute to the septa and valves of the mature heart and receive cell populations from neural crest (NC) cell migration and epicardial cell invasion. We examined embryonic chick hearts for expression, in the cushions, of bcl-2 family members, caspase-9, and the caspase substrate poly(ADP-ribose) polymerase. Antiapoptotic bcl-2 is expressed heavily in the OT and AV regions throughout embryonic days (ED) 4-7, with a decrease in levels at ED 4 and 5 in OT and AV cushions, respectively. Proapoptotic bax predominantly associated with the prongs of the NC-derived aorticopulmonary (AP) septum but was expressed throughout the AV cushions. Proapoptotic bak also associated with the prongs of the AP septum in the OT, while protein levels were upregulated at ED 4-5 and 4-6 in OT and AV cushions, respectively. Bid expression showed a similar time course. We found the 10-kDa cleavage fragment of active caspase-9 at ED 4-8 and 5-8 in OT and AV cushions, respectively, and the 24-kDa cleavage fragment of poly(ADP-ribose) polymerase throughout ED 3-8 and 7-8 in OT and AV cushions, respectively. Caspase-3 cleavage occurred throughout the time period examined. Using cushion cell cultures, we found that inhibitors of caspases-3 and -9 and a universal caspase inhibitor significantly reduced apoptosis, as did retroviral overexpression of bcl-2 using an RCAS expression vector. Premigratory NC cells were fluorescently labeled in vivo with 1,1-didodecyl-3,3,3',3'-tetramethylindocarbocyanine. Subsequent nuclear staining of cushion cells with 4,6-diamidino-2-phenylindole revealed the presence of apoptotic nuclei in the NC cells in the OT cushions and in the prongs of the AP septum. These results demonstrate a developmentally regulated role for the bcl-2 and the caspase families of molecules in the endocardial cushions of the developing heart and lend support to the possibility that some of the dying cells in the cushions are derived from the NC.
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PMID:Regulation of apoptosis in the endocardial cushions of the developing chick heart. 1199 50

Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to produce an anti-proliferative and pro-apoptotic effect on different types of cancer cell lines. Previously, we demonstrated that high dose of NS-398 (100 microM), a selective cyclooxygenase-2 inhibitor, induced a cell cycle slowing or arrest and, in contrast to low dose (10 microM), a marked decrease in apoptosis in human 1547 osteosarcoma cells. In this study, we investigated particularly the effect of 100 microM NS-398 on p53 and p21 expression, caspase activities and nuclear factor-kappaB (NF-kappaB). We found a correlation between p53, p21 mRNA expression and NF-kappaB activation and, we observed an induction of heat shock protein 70 expression with a large decrease in caspase-3 activity after 100 microM NS-398 treatment. Moreover, the inhibition of apoptosis was correlated with an increase in bcl-2/bax ratio. Our new findings confirm the novel anti-apoptotic property of NS-398 at 100 microM, as we previously found, which contrasts to the described NS-398 pro-apoptotic effect on other cancer cell lines.
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PMID:The anti-apoptotic property of NS-398 at high dose can be mediated in part through NF-kappaB activation, hsp70 induction and a decrease in caspase-3 activity in human osteosarcoma cells. 1201 7

Methamphetamine is a neurotoxic drug of abuse known to cause cell death both in vitro and in vivo. Nevertheless, the molecular and cellular mechanisms involved in this process remain to be clarified. Herein, we show that methamphetamine-induced apoptosis is associated with early (2 h) overexpression of bax, decreases of mitochondrial membrane potential and oxygen consumption as well as release of cytochrome c from mitochondria. In addition, activated caspase-9 was detected at 4 h post-METH exposure. Cell death was detectable by annexin V and propidium iodide staining after 8 h of methamphetamine exposure. At that time, the majority of the cells were stained by annexin V alone, with some cells being stained for both annexin V and propidium iodide. Moreover, cleavage of caspase-3, poly (ADP-ribose) polymerase and DNA fragmentation-related factor 45 was detected at 8 h post drug treatment. These results indicate that methamphetamine-induced apoptotic cell death results from early overexpression of bax, reduction of mitochondrial respiration and membrane potential and release of mitochondrial cytochrome c with subsequent activation of the caspase cascade.
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PMID:Methamphetamine induces apoptosis in an immortalized rat striatal cell line by activating the mitochondrial cell death pathway. 1201 10

To investigate whether amiodarone induces apoptosis in cells of the L-132 human lung epithelial cell line, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, 4,6-diamidino-2-phenylindole staining, DNA fragmentation assay, reverse transcription-polymerase chain reaction, and casapse-3 enzyme assay were performed. Through morphological and biochemical analyses, it was demonstrated that L-132 cells treated with amiodarone exhibit several features of apoptosis. In addition, it was shown that amiodarone increases the mRNA levels of bax and caspase-3. Based on the results, amiodarone appears to activate specific intracellular death-related pathways, including possibly the bax-dependent caspase-3 activation pathway, and thus induce apoptosis in human lung epithelial cells.
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PMID:Amiodarone induces apoptosis in L-132 human lung epithelial cell line. 1208 19

We have studied the effect of N-(4-hydroxyphenyl)retinamide on either malignant human leukaemia cells or normal cells and investigated its mechanism of action. We demonstrate that 4HPR induces reactive oxygen species increase on mitochondria at a target between mitochondrial respiratory chain complex I and II. Such oxidative stress causes cardiolipin peroxidation which in turn allows cytochrome c release to cytosol, caspase-3 activation and therefore apoptotic consumption. Moreover, this apoptotic pathway seems to be bcl-2/bax independent and count only on malignant cells but not normal nor activated lymphocytes.
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PMID:Implication of mitochondria-derived ROS and cardiolipin peroxidation in N-(4-hydroxyphenyl)retinamide-induced apoptosis. 1208 92

Our objective was to identify shed placental plasma membrane fragments in the maternal circulation and determine whether these fragments are capable of down-regulating CD3-zeta chain expression and inducing apoptosis in T lymphocytes. Sera, isolated from the blood of pregnant women at 26-29 weeks gestation that subsequently had uncomplicated term deliveries, were subjected to high exclusion-limit gel chromatography to isolate placental membrane fragments. The placental origin of the fragments was confirmed by the presence of placental-type alkaline phosphates. These shed membrane fragments were further analyzed for the presence of Fas ligand (FasL) and modulation of CD3-zeta expression on cultured T-lymphocytes (Jurkat cells). The ability of the shed membrane fragments to induce apoptosis was assayed using a cell death ELISA. Components associated with Fas-dependent apoptosis (caspase-3, bcl-2 and bax) were characterized using western immunoblot following exposure to serum-derived membrane fragments. Placental membrane fragments were identified in all pregnancy sera, but not in non-pregnant controls. The 41 kDa FasL was identified in membrane fragment isolates and all samples were capable of inducing apoptosis as determined by the ELISA assay. Exposure of T lymphocytes to isolated membrane fragments suppressed the expression of CD3-zeta. The induction of apoptosis correlated with the induction and activation of caspase 3 and the induction of bax. Placenta-derived membrane fragments are detectable in the maternal circulation. These membrane fragment isolates are capable of inducing FasL-mediated apoptosis and down-regulating CD3-zeta expression, which may contribute to the immune tolerance of the fetus.
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PMID:Shed membrane fragment modulation of CD3-zeta during pregnancy: link with induction of apoptosis. 1210 82

Reactive changes in free intracellular zinc cation concentration ([Zn(2+)](i)) were monitored, using the fluorescent probe Zinquin, in human lymphoma cells exposed to the DNA-damaging agent VP-16. Two-photon excitation microscopy showed that Zinquin-Zn(2+) forms complexes in cytoplasmic vesicles. [Zn(2+)](i) increased in both p53(wt) (wild type) and p53(mut) (mutant) cells after exposure to low drug doses. In p53(mut) cells noncompetent for DNA damage-induced apoptosis, elevated [Zn(2+)](i) was maintained at higher drug doses, unlike competent p53(wt) cells that showed a collapse of the transient before apoptosis. In p53(wt) cells, the [Zn(2+)](i) rise paralleled an increase in p53 and bax-to-bcl-2 ratio but preceded an increase in p21(WAF1), active cell cycle arrest in G(2), or nuclear fragmentation. Reducing [Zn(2+)](i), using N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine, caused rapid apoptosis in both p53(wt) and p53(mut) cells, although cotreatment with VP-16 exacerbated apoptosis only in p53(wt) cells. This may reflect changed thresholds for proapoptotic caspase-3 activation in competent cells. We conclude that the DNA damage-induced transient is p53-independent up to a damage threshold, beyond which competent cells reduce [Zn(2+)](i) before apoptosis. Early stress responses in p53(wt) cells take place in an environment of enhanced Zn(2+) availability.
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PMID:DNA damage-induced [Zn(2+)](i) transients: correlation with cell cycle arrest and apoptosis in lymphoma cells. 1210 71

The influence of zinc status on the levels of p53, as well as downstream targets of p53 in cell repair and survival, was examined in human aortic endothelial cells (HAECs). A serum-reduced low-zinc medium (ZD) was used to deplete zinc over one passage. Other treatments included zinc-normal control (ZN), zinc-adequate (ZA), and zinc-supplemented (ZS) treatment with 3.0, 16.0, and 32.0 microM zinc, respectively. Cellular zinc levels in the ZD cells were 64% of ZN controls; levels in the ZA cells were not different, but levels in ZS cells were significantly higher (40%) than in ZN cells. No difference in p53 mRNA abundance was detected among all treatments; however, p53 nuclear protein levels were >100% higher in the ZD and ZS cells and almost 200% higher in the ZA cells than in ZN controls. In addition, p21 mRNA abundance, a downstream target of p53 protein, was increased in the ZS cells compared with both the ZN control and ZD cells. In the ZS cells, bax and mcl-1 were also approximately 50% higher compared with ZN controls, whereas bcl-2 mRNA was increased compared with ZA cells. Moreover, caspase-3 activity of ZD cells was not different from that of ZN controls but was reduced to 83 and 69% of ZN controls in ZA and ZS cells, respectively. Thus p53 protein and p53 downstream target genes appeared to be modulated by intracellular zinc status in HAECs.
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PMID:p53 protein and p21 mRNA levels and caspase-3 activity are altered by zinc status in aortic endothelial cells. 1210 73


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