Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

L-Arginine is the common substrate for two enzymes, arginase and nitric oxide synthase (NOS). Arginase converts L-arginine to L-ornithine, which is the precursor of polyamines, which are essential components of cell proliferation. NOS converts L-arginine to produce NO, which inhibits proliferation of many cell lines. Various human breast cancer cell lines were initially screened for the presence of arginase and NOS. Two cell lines, BT-474 and MDA-MB-468, were found to have relatively high arginase activity and very low NOS activity. Another cell line, ZR-75-30, had the highest NOS activity and comparatively low arginase activity. The basal proliferation rates of MDA-MB-468 and BT-474 were found to be higher than the ZR-75-30 cell line. N-Hydroxy-L-arginine (NOHA), a stable intermediate product formed during conversion of L-arginine to NO, inhibited proliferation of the high arginase-expressing MDA-MB-468 cells and induced apoptosis after 48 h. NOHA arrested these cells in the S phase, increased the expression of p21, and reduced spermine content. These effects of NOHA were not observed in the ZR-75-30 cell line, which expresses high NOS and relatively low arginase. The effects of NOHA were antagonized in the presence of L-ornithine (500 microM), which suggests that in MDA-MB-468 cell line, the arginase pathway is very important for cell proliferation. Inhibition of the arginase pathway led to depletion of intracellular spermine and apoptosis as observed by terminal deoxynucleotidyl transferase (Tdt)-mediated nick end labeling assay and induction of caspase 3. In contrast, the ZR-75-30 cell line maintained its viability and its L-ornithine and spermine levels in the presence of NOHA. We conclude that NOHA has antiproliferative and apoptotic actions on arginase-expressing human breast cancer cells that are independent of NO.
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PMID:Arginase activity in human breast cancer cell lines: N(omega)-hydroxy-L-arginine selectively inhibits cell proliferation and induces apoptosis in MDA-MB-468 cells. 1086 25

4-Hydroxy-2,3-trans-nonenal (HNE) is a neurotoxic unsaturated aldehyde end-product of lipid peroxidation. The addition of HNE to NT-2 and SK-N-MC cell lines induces apoptosis and we now investigated the time-course of events occurring prior to apoptosis. Treatment of both NT-2 and SK-N-MC cell lines with HNE led to HNE association with the proteasome, increased levels of protein carbonyls and ubiquitinated proteins, and decreased proteasomal function. There was also decreased metabolic activity, cytochrome c release and activation of caspase 3, followed by apoptotic changes including chromatin condensation, cell shrinkage and DNA fragmentation and laddering. Overexpression of mutant superoxide dismutase 1 proteins associated with amyotrophic lateral sclerosis decreased proteasomal activities in the absence of HNE and accelerated the apoptosis induced by HNE. By contrast, overexpression of wild-type superoxide dismutase 1 did not affect basal levels of proteasomal activity. The data suggest that accumulation of ubiquitinated proteins and impairment of proteasomal function are important events in HNE toxicity. We propose that the proteasomal system is a significant target of HNE neurotoxicity in a wide range of neurodegenerative diseases, especially if abnormal proteins are being expressed.
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PMID:Proteasomal dysfunction induced by 4-hydroxy-2,3-trans-nonenal, an end-product of lipid peroxidation: a mechanism contributing to neurodegeneration? 1242 46

We investigated the effect of a series of Maillard reaction products formed from carbohydrates under household heating conditions on the growth of human tumor cells in vitro. 4-Hydroxy-5-methyl-3-(2H)-furanone (1) was found to potently enhance the proliferation of human tumor cells. In contrast, the Maillard-type chromophores 2-(2-furyl)methylidene-4-hydroxy-5-methyl-2H-furan-3-one (2), 4-(2-furyl)-7-[(2-furyl)methylidene]-2-hydroxy-2H,7H,8aH-pyrano[2,3-b]- pyran-3-one (6), and 3-hydroxy-4[(E)-(2-furyl)methylidene]methyl-3-cyclopentene-1,2 dione (13) inhibited the growth of human tumor cells in vitro in the low micromolar range. GXF251L cells (gastric carcinoma), synchronized by serum deprivation, were retained in the G1-phase of the cell cycle after treatment with 2, 6, or 13 for 24 h. Concomitantly, a distinct sub-G1 peak was observed, indicative for apoptosis induction. DNA fragmentation was further investigated by ELISA using antibodies raised against histones and DNA. 2 induced a significant increase of fragmented DNA at concentrations > or = 30 microM. After treatment with compound 6, DNA fragmentation was observed at a higher concentration range (> or = 50 microM), whereas incubation with 13 resulted in a marked DNA fragmentation already at 20 microM. On the protein level, the activation of caspase 3, as an early marker for apoptosis induction, was determined. The results were almost identical to those obtained in the DNA fragmentation ELISA. In summary, Maillard reaction products potently modulating the growth of human tumor cells were identified. The Maillard-type chromophores 2, 6, and 13 were found to interfere with the proliferation of gastric carcinoma cells, causing cell cycle arrest and apoptosis induction.
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PMID:Maillard reaction products modulating the growth of human tumor cells in vitro. 1269 30

The proinflammatory cytokines tumor necrosis factor (TNFalpha), interleukin-1 (IL-1alpha), and interleukin-6 (IL-6) have been associated with various models of hippocampal damage. To examine their role in initiation of an acute hippocampal injury response, 21-day-old male CD-1 mice received an acute intraperitoneal (i.p.) injection of trimethyltin hydroxide (TMT; 2.0 mg/kg) to produce necrosis of dentate granule neurons, astrocyte, and microglia reactivity. Tremors and intermittent seizures were evident at 24 hr. Intercellular adhesion molecule-1 (ICAM-1), glial fibrillary acidic protein (GFAP), anti-apoptotic TNFalpha-inducible early response gene (A-20), macrophage inflammatory protein (MIP)-1alpha, TNFalpha, IL-1alpha, IL-6, and caspase 3 mRNA levels were significantly elevated. Pretreatment with the antioxidant, ebselen, decreased ICAM-1, A-20, and TNFbeta elevations. Pentoxifylline blocked elevations in A-20 and decreased elevations in GFAP mRNA levels. Neither prevented histopathology or behavioral effects. Intracisternal injection of TNFalpha-neutralizing antibody significantly inhibited both behavioral effects and histopathology. RNase protection assays showed that TMT-induced elevations in mRNA levels for ICAM-1, A-20, GFAP, MIP-1alpha, IL-1alpha, TNFalpha, TNFbeta, and caspase 3 were blocked by anti-TNFalpha. These data demonstrate a significant role for TNFalpha in an acute neuro-injury in the absence of contribution from infiltrating cells. The cerebellum shows limited if any damage after TMT; however, in combination with the i.c.v. injection, elevations were seen in GFAP and in EB-22, a murine acute-phase response gene homologous to the alpha (1)-antichymotrypsin gene. Elevations were similar for artificial cerebral spinal fluid and anti-IL-1alpha, and significantly increased with anti-TNFalpha, anti-IL-6, or the combination of antibodies. Responses seen in the cerebellum suggest synergistic interactions between the baseline state of the cell and manipulations in the cytokine environment. Data suggests a role for TNFalpha in the pathogenesis of hippocampal injury induced by TMT.
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PMID:Differential modulation of hippocampal chemical-induced injury response by ebselen, pentoxifylline, and TNFalpha-, IL-1alpha-, and IL-6-neutralizing antibodies. 1289 37

3-Hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) are effective in patients with hypercholesterolemia to reduce risk of cardiovascular diseases, because of not only their lowering cholesterol effects but also their pleiotropic effects, such as improvement of endothelial cell dysfunction. On the other hand, statins prevent cell proliferation of various cells, including endothelial cells. We examined effects of all statins available at present on the viability of cultured rat pulmonary vein endothelial cells. Lovastatin, simvastatin, atorvastatin, fluvastatin and cerivastatin, which are hydrophobic statins, markedly reduced cell viability associated with DNA fragmentation, DNA laddering and activation of caspase-3, suggesting apoptotic cell death. Pravastatin, which is a hydrophilic statin, however, did not induce cell apoptosis. Apoptosis induced by hydrophobic statins was associated with activation of apoptosis-related intracellular signal transduction systems; attenuation of localization of RhoA to the membrane, induction of Rac1, and increase in phosphorylation of c-Jun N-terminal kinase and c-Jun. Endothelial cell apoptosis is underlying the improvement of the endothelial dysfunction with hydrophobic statins.
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PMID:All hydrophobic HMG-CoA reductase inhibitors induce apoptotic death in rat pulmonary vein endothelial cells. 1461 3

Low doses, chronic exposure to mercurial organic compounds is a worldwide health concern and could be pathogenetically relevant as co-factor in several neurodegenerative diseases. In this in vitro study we wanted to further improve our knowledge on the mechanisms of toxicity of methylmercury hydroxide (MeHgOH) in the unprimed PC12 cell line. Cell viability, mitochondrial function, redox state, and cell morphology were recorded at different time points to sequence the events leading to cell death. The lowest cytotoxic concentration and EC50 were 0.3 and 1.3 microM, respectively. 5 microM MeHgOH was fatal for 80% of the cell population after 24 h; within 1 h it caused glutathione (GSH) depletion and a partial dissipation of Deltapsim. At this concentration, reactive oxygen species (ROS) generation was only slight and delayed. After 6h more than 50% of ATP was available and caspase 3 was active. Time-lapse confocal microscopy showed that only a fraction of the cells completed apoptosis while others turned toward necrosis (necrapoptosis). Pre-incubation with N-acetylcysteine (NAC) and GSH but not Cyclosporin A rescued over 80% of the cells. These results provide experimental evidence that, in this cell model, MeHgOH triggers cell death via a primary depletion of GSH but in the absence of ROS overproduction.
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PMID:Methylmercury cytotoxicity in PC12 cells is mediated by primary glutathione depletion independent of excess reactive oxygen species generation. 1538 43

2-(8-Hydroxy-6-methoxy-1-oxo-1Eta-2-benzopyran-3-yl)propionic acid (NM-3) is a small molecule isocoumarin derivative that has recently entered clinical trials as an orally bioavailable anticancer agent. NM-3 induces lethality of human carcinoma cells by both apoptotic and nonapoptotic mechanisms and potentiates the effects of cytotoxic chemotherapeutic agents. The present studies have evaluated the effects of NM-3 on human multiple myeloma (MM) cells. The results demonstrate that NM-3 potentiates dexamethasone-induced killing of both dexamethasone-sensitive MM1.S and dexamethasone-resistant RPMI8226 and U266 MM cells. We show that NM-3 enhances dexamethasone-induced release of the mitochondrial apoptogenic factors cytochrome c and Smac/DIABLO. The results also demonstrate that NM-3 enhances dexamethasone-induced activation of the intrinsic caspase-9->caspase-3 apoptotic pathway. In concert with these results, NM-3 potentiates dexamethasone-induced apoptosis of MM1.S cells. Moreover, NM-3 acts synergistically with dexamethasone in inducing apoptosis of the dexamethasone-resistant RPMI8226 and U266 MM cells. These findings indicate that NM-3 may be effective in combination with dexamethasone in the treatment of MM.
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PMID:2-(8-Hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-yl)propionic acid, a small molecule isocoumarin, potentiates dexamethasone-induced apoptosis of human multiple myeloma cells. 1557 55

The role of biomembranes in the chronic toxicity of environmentally occurring chromium acetate hydroxide was investigated by using primary human fibroblasts. Transport of chromium acetate hydroxide across the plasma membrane of the cell, and the effects of chromium (III) ions on the plasma membrane as well as other intracellular membranes, were determined during six weeks of continuous exposure by using atomic absorption spectrometry, observation of cell morphology, membrane integrity assays (for lactate dehydrogenase leakage and lysosomal membrane disruption), and mitochondrial assays (for mitochondrial dehydrogenase activity and mitochondrial transmembrane potential analysis). The type of cell death induced by long-term exposure was determined in terms of phosphatidylserine externalisation, caspase-3 activation, and chromatin fragmentation. Chromium acetate hydroxide, at a concentration of 100 micromol/l, accumulated in exposed cells, inflicting plasma membrane damage and suppressing mitochondrial function. Antioxidant co-enzyme Q, at a concentration of 10 micromol/l, partially prevented plasma membrane damage and mitochondrial dysfunction. Exposure to chromium acetate hydroxide produced apoptosis, necrosis and an intermediate type of cell death in primary human fibroblasts. These results show that the plasma membrane and mitochondrial membrane are important targets for chronic chromium acetate hydroxide toxicity, and that this in vitro system holds promise for studying the toxicity resulting from long-term exposure to metal ions.
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PMID:The role of biomembranes in chromium (III)-induced toxicity in vitro. 1618 Sep 79

3beta-Hydroxy-12-oleanen-27-oic acid (ATA) was an antitumor active oleanane-type triterpenoid from the rhizomes of Astilbe chinensis. ATA was structurally very similar to oleanolic acid, with the only difference being interchange of the carboxyl and methyl group at the C-14 and C-17 positions. Oleanane-type triterpene with a carboxyl group at C-14 is present in a limited number of natural resources. ATA was found to exhibit more distinctive cytotoxicity toward human cervical squamous carcinoma HeLa cells than oleanolic acid, which suggested that the position of the carboxyl group significantly affects the cytotoxicity of oleanane-type pentacyclic triterpenes with a carboxyl group. The biological mechanism responsible for the cytotoxicity of ATA is not yet well understood. In this study, we investigated the induction of apoptosis in HeLa cells by ATA and the putative pathways of its actions. ATA induced a marked concentration- and time-dependent inhibition of HeLa cell proliferation, and reduced the protein content in HeLa cells. ATA-treated HeLa displayed typical morphological apoptotic characteristics and formation of DNA ladders in agarose gel electrophoresis. Flow cytometric analysis showed that the HeLa cell cycle was arrested in the G(0)/G(1) phase by ATA, and the apoptotic rate of HeLa cells treated with ATA 20 microg/mL for 48 h was 22.63 +/- 1.65%. Meanwhile, ATA increased the expression of Bax, decreased the expression of Bcl-2, and lowered the DeltaPsi(m). DEVD-CHO 2 microM could increase the viability of ATA-treated HeLa cells. These results indicate that ATA could significantly induce cell apoptosis through down-regulating Bcl-2 expression, up-regulating Bax expression, lowering DeltaPsi(m), and activating the caspase-3 pathway, and should be useful in the search for new potential anti-tumor agents and for developing semisynthetic oleanane-type triterpene derivatives with anti-tumor activity.
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PMID:Induction of apoptosis in HeLa cells by 3beta-hydroxy-12-oleanen-27-oic acid from the rhizomes of Astilbe chinensis. 1621 53

We have shown previously that down-regulation of CK2 activity (protein kinase CK2, formerly casein kinase 2) by employing its inhibitors apigenin or 4,5,6,7-tetrabromobenzotriazole promotes apoptosis in prostatic carcinoma cells. In an effort to define the downstream mediators of this action, we show that cell apoptosis observed on down-regulation of CK2 is preceded by intracellular generation of hydrogen hydroxide (H2O2) in various normal and cancer cells. In this regard, both androgen-dependent ALVA-41 and androgen-independent PC-3 cells treated with 80 micromol/L apigenin or 4,5,6,7-tetrabromobenzotriazole or with antisense CK2alpha oligonucleotide or small interfering RNA respond similarly to down-regulation of CK2. Interestingly, whereas chemical inhibitors of CK2 elicited H2O2 production in both cancer and noncancer cells, the antisense CK2alpha-mediated down-regulation of CK2 showed significant H2O2 production in cancer cells but had minimal effect in noncancer cells. The basis of this key difference is unclear at present, but this observation may have implications for the therapeutic potential of antisense CK2 oligonucleotide in cancer therapy. The H2O2 production induced by antisense CK2alpha was associated with robust caspase-3 activity, nuclear factor-kappaB nuclear translocation, cytochrome c release, and subsequent DNA fragmentation in prostate cancer cells (ALVA-41 and PC-3). These findings describe, for the first time, a relationship between CK2 and reactive oxygen species, such that CK2 inhibition leads to production of intracellular H2O2, which may serve as a downstream mediator of apoptosis in cancer cells.
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PMID:Intracellular hydrogen peroxide production is an upstream event in apoptosis induced by down-regulation of casein kinase 2 in prostate cancer cells. 1668 88


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