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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cadmium (Cd) and chromium (Cr) are human carcinogens. Cr(VI) is taken up into cells and reduced by cellular reductants to the potential DNA damaging species Cr(V), (IV), and (III). Reactive oxygen species and carbon-based radicals may also be produced during Cr reduction. We previously found that Cd blocks Cr-induced apoptosis, which could allow a larger proportion of genetically damaged cells to escape and become transformed. This study helped define the mechanisms of Cd-induced suppression of apoptosis. Chinese hamster ovary (CHO K1-BH4) cells were treated with either Cd (5-20 microM), Cr(VI) (350 microM), or Cd (5-20 microM) plus Cr(VI) (350 microM) for 3 h and then cultured in metal-free media for an additional 48 h at which time DNA was extracted or nuclei were examined to determine apoptosis. Cd markedly reduced Cr-induced DNA fragmentation and reduced the number of Cr-induced apoptotic cell nuclei to control levels. Additional study investigated the biokinetics and cellular metabolism of Cr. Cd did not alter the cellular Cr accumulation and there were no differences in the levels of reduced glutathione, a compound possibly important in Cr reduction and reflective of the cellular reducing environment. The antiapoptotic effect of Cd was not due to diminished cellular reduction of Cr(VI) as assessed by electron-spin resonance determination of the levels of Cr(V). Thus, Cd suppression of Cr-induced apoptosis is not based on altered Cr toxicokinetics or metabolism. In addition to Cr, Cd also inhibited apoptosis induced by hygromycin B and actinomycin D. Cd was a very effective inhibitor of caspase-3 activity, a central mediator of apoptosis, with nontoxic levels of Cd resulting in up to approximately 60% inhibition. These results indicate that Cd may have a generalized inhibitory effect on apoptosis, possibly by inhibiting caspase-3. Inhibition of apoptosis by Cd may allow a greater portion of genetically damaged cells to survive, or give selective growth advantages, and has implications as a potential nongenotoxic mechanism of Cd carcinogenesis.
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PMID:Possible role of caspase-3 inhibition in cadmium-induced blockage of apoptosis. 1079 43

To delineate the molecular mechanisms of NF-kappaB-mediated regulation of chromium(VI)-induced cell death, the signaling pathway leading to the activation of NF-kappaB was interrupted by stable transfection of a kinase-mutated form of IkappaB kinase beta (IKKbeta-KM). Here we demonstrate a novel role for the NF-kappaB transcription factor in inhibiting chromium(VI)-induced cell death. Inhibition of NF-kappaB by IKKbeta-KM or IKKbeta gene deficiency resulted in a spontaneous cleavage of Bcl-xL antiapoptotic protein due to the elevated caspase-3 activity. DNA microarray assay suggested a decreased expression of genes encoding antiapoptotic proteins, cIAP1 and cIAP2, in the cells overexpressing IKKbeta-KM. Chromium(VI) treatment of these NF-kappaB-inhibited cells induced necrotic-like cell death. Such chromium(VI)-induced cell killing could be partially inhibited by expression of exogenous cIAP1, an inhibitor of caspases, indicating that caspases along with others may be involved in chromium(VI)-induced cell death. These results suggest that NF-kappaB is essential for inhibiting toxic metal-induced cytotoxicity. Such inhibition may involve up-regulation of the expression of anti-death proteins including cIAP1 that prevents spontaneous caspase activation and subsequent cleavage of Bcl-xL protein.
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PMID:Protective roles of NF-kappa B for chromium(VI)-induced cytotoxicity is revealed by expression of Ikappa B kinase-beta mutant. 1172 46

Fanconi anemia (FA) is an autosomal recessive disorder characterized by diverse developmental abnormalities, progressive bone marrow failure, and a markedly increased incidence of malignancy. FA cells are hypersensitive to DNA cross-linking agents, suggesting a general defect in the repair of DNA cross-links. Some forms of hexavalent chromium [Cr(VI)] are implicated as respiratory carcinogens and induce several types of DNA lesions, including ternary DNA-Cr-DNA interstrand cross-links (Cr-DDC). We hypothesized that human FA complementation group A (FA-A) cells would be hypersensitive to Cr(VI) and Cr(VI)-induced apoptosis. Using phosphatidylserine translocation and caspase-3 activation, human FA-A fibroblasts were found to be markedly hypersensitive to chromium-induced apoptosis compared with CRL-1634 cells, which are normal human foreskin fibroblasts (CRL). The clonogenicity of FA-A cells was also significantly decreased compared with CRL cells after Cr(VI) treatment. There was no significant difference in either Cr(VI) uptake or Cr-DNA adduct formation between FA-A and CRL cells. These results show that FA-A cells are hypersensitive to Cr(VI) and Cr-induced apoptosis and that this hypersensitivity is not due to increased Cr(VI) uptake or increased Cr-DNA adduct formation. The results also suggest that Cr-DDC may be proapoptotic lesions. These results are the first to show that FA cells are hypersensitive to an environmentally relevant DNA cross-linking agent.
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PMID:Fanconi anemia complementation group A cells are hypersensitive to chromium(VI)-induced toxicity. 1242 30

Mechanistic insights into Cr(VI)-induced carcinogenicity and possible implication of Cr(V) species formed by the redox reactions of chromium-bearing species have attracted interest. We have previously demonstrated that when human peripheral blood lymphocytes are exposed to the Cr(V) complexes, viz., sodium bis(2-ethyl-2-hydroxybutyrato)oxochromate(V), Na[Cr(V)O(ehba)(2)] and sodium bis(2-hydroxy-2-methylbutyrato)oxochromate(V), Na[Cr(V)O(hmba)(2)], apoptosis and formation of reactive oxygen species (ROS) are observed. The molecular mechanisms involving cellular signaling pathways leading to apoptosis are addressed in the present study. Treatment of lymphocytes with Na[Cr(V)O(ehba)(2)] and K(2)Cr(2)O(7) leads to the activation of the Src-family protein tyrosine kinases namely, p56(lck), p59(fyn), and p56/53(lyn), which then activates caspase-3, both of which are under the partial influence of ROS. Inhibition of the Src-family tyrosine kinases activity by PP2 and of caspase-3 by Z-DEVD-FMK reverses apoptosis, thereby suggesting their importance. Antioxidants only partially reverse the apoptosis induced by Cr(VI/V), suggesting that pathways other than those induced by ROS cannot be ruled out. Although the complex, Na[Cr(V)O(ehba)(2)] is known to be relatively stable in aqueous solutions, previous studies have shown that the Cr(V) complex, Na[Cr(V)O(ehba)(2)] disproportionates to Cr(VI) and Cr(III) forms at pH 7.4 through complex mechanistic processes. Dynamics studies employing EPR data show that the Cr(V) state in Na[Cr(V)O(ehba)(2)] is relatively more stable in RPMI-1640 medium containing plasma. Formation of ROS during the reaction of redox partners with Na[Cr(V)O(ehba)(2)] is an early event and compares favorably in kinetic terms with the reported rate processes for disproportionation. This investigation presents evidence for the direct implication of Cr(V) in Cr(VI)-induced apoptosis of lymphocytes.
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PMID:Apoptosis of lymphocytes induced by chromium(VI/V) is through ROS-mediated activation of Src-family kinases and caspase-3. 1457 11

In order to investigate the low-dose long-term Cr(VI) action on antioxidant enzymes in cultured mammalian cells we estimated the activity of glutathione dependent antioxidant enzymes, catalase and superoxide dismutase (SOD) under various chromium concentrations in human epithelial-like L-41 cells. The long-term action of 20 microM causes the toxicity that results in losing of the cell viability by activating the apoptotic process, as identified by morphological analysis, the activation of caspase-3, and DNA fragmentation. The toxic chromium concentration totally destroys glutathione antioxidant system, and diminishes the activity of catalase and cytosolic Cu, ZnSOD. The non-toxic concentration (2 microM) causes the activation of the antioxidant defense systems, and they neutralize the oxidative impact.
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PMID:Effects of Cr(VI) long-term and low-dose action on mammalian antioxidant enzymes (an in vitro study). 1498 50

In this study, we have examined the role of caspase-3 in apoptosis of lymphocytes induced by the chromium(III) complexes viz. tris-(1,10-phenanthroline)chromium(III) chloride (Cr(III)-phen) and trans-diaqua[1,3-bis(salicylideneamino)propanechromium(III)] perchlorate (Cr(III)-salprn). Evidence for caspase-3 activation and poly(ADP-ribose) polymerase (PARP) cleavage in lymphocytes exposed to Cr(III) complexes is revealed through Western blotting analysis. Blocking the activity of caspase-3 with z-DEVD-fmk, prevents apoptosis as evidenced through [3H]-thymidine incorporation, DNA fragmentation assay and measurement of sub-G1 cells by flow cytometry. Pretreatment of lymphocytes with free radical scavengers completely attenuates the activity of caspase-3 suggesting that reactive oxygen species (ROS) are upstream activators of caspase-3. Preincubation of lymphocytes with PP2, a selective Src-family tyrosine kinase inhibitor, abolishes the activation of caspase-3 indicating that Src-family tyrosine kinases viz. p56lck, p59fyn and p53/56lyn are mediators of caspase-3 activation during Cr(III) exposure. Collectively, our findings support a plausible mechanism in which Cr(III) mediates ROS generation that precedes the up-regulation of p56lck, p59fyn and p53/56lyn which eventually activates caspase-3 to promote apoptotic cell death of lymphocytes. To our knowledge, this is the first report suggesting the importance of Src-family tyrosine kinases for the activation of caspase-3 in metal-induced apoptotic cell death.
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PMID:Caspase-3: its potential involvement in Cr(III)-induced apoptosis of lymphocytes. 1512 6

It has been reported that the hexavalent chromium compound (Cr(VI)) can induce both p53-dependent and p53-independent apoptosis. While a considerable amount of information is available on the p53-dependent pathway, only little is known about the p53-independent pathway. To elucidate the p53-independent mechanism, the roles of the Ca(2+)-calpain- and mitochondria-caspase-dependent pathways in apoptosis induced by Cr(VI) were investigated. When human lymphoma U937 cells, p53 mutated cells, were treated with 20 microM Cr(VI) for 24 h, nuclear morphological changes and DNA fragmentation were observed. Production of hydroxyl radicals revealed by electron paramagnetic resonance (EPR)-spin trapping, and increase of intracellular calcium ion concentration monitored by digital imaging were also observed in Cr(VI)-treated cells. An intracellular Ca(2+) chelator, BAPTA-AM, and calpain inhibitors suppressed the Cr(VI)-induced DNA fragmentation. The number of cells showing low mitochondrial membrane potential (MMP), high level of superoxide anion radicals (O(2)(-)), and high activity of caspase-3, which are indicators of mitochondria-caspase-dependent pathway, increased significantly in Cr(VI)-treated cells. An antioxidant, N-acetyl-l-cysteine (NAC), decreased DNA fragmentation and inhibited the changes in MMP, O(2)(-) formation, and activation of caspase-3 induced by Cr(VI). No increase of the expressions of Fas and phosphorylated JNK was observed after Cr(VI) treatment. Cell cycle analysis revealed that the fraction of G2/M phase tended to increase after 24 h of treatment, suggesting that Cr(VI)-induced apoptosis is related to the G2 block. These results indicate that Ca(2+)-calpain- and mitochondria-caspase-dependent pathways play significant roles in the Cr(VI)-induced apoptosis via the G2 block, which are independent of JNK and Fas activation. The inhibition of apoptosis and all its signal transductions by NAC suggests that intracellular reactive oxygen species (ROS) are important for both pathways in Cr(VI)-induced apoptosis of U937 cell.
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PMID:Signal transduction of p53-independent apoptotic pathway induced by hexavalent chromium in U937 cells. 1516 45

The aim of this study was to evaluate the cytotoxic and apoptotic effects of cobalt and chromium ions on macrophages in vitro, and analyze the implication of caspase-3 in the apoptotic pathway. J774 mouse macrophages (5 x 10(5) cells/ml) were exposed for up to 24 h to 0-10 ppm Co2+ and 0-500 ppm Cr3+. The cytotoxic effect of ions was measured by Trypan blue exclusion. DNA analysis on agarose gel was used as a specific test for detection of DNA fragmentation into oligonucleosomes that occurs in apoptotic cells. The proteolytic cleavage of poly(ADP-ribose)polymerase (PARP), closely associated with the induction of apoptosis, was also analyzed along with the appearance of the active fragment of caspase-3, implicated in several apoptosis pathways. Results demonstrated that both Co2+ and Cr3+ ions induce macrophage mortality in a dose-dependent manner. However, Co2+ is more toxic inducing a cell mortality up to 28% with only 10 ppm vs. 37% with 500 ppm of Cr3+. DNA analysis demonstrated that both Co2+ and Cr3+ ions induce DNA fragmentation, between 6-10 ppm Co2+ and 250-500 ppm Cr3+ after 24 h incubation. PARP cleavage and the appearance of caspase-3 active fragment were observed after 6 h with both Co+ and Cr3+ ions, with a stronger signal after 24 h and 10 ppm of Co2+ or 500 ppm of Cr3+. In conclusion, this study demonstrates that after 24 h incubation, both Co2+ and Cr3+ ions can induce macrophage mortality, and more specifically apoptosis. The results also suggest that apoptosis occurs via a caspase-3 pathway. However, the relative importance of necrosis and apoptosis and the effects of longer exposure times on the induction of macrophage death by these metal ions remain to be investigated.
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PMID:Cytotoxic and apoptotic effects of cobalt and chromium ions on J774 macrophages - Implication of caspase-3 in the apoptotic pathway. 1534 46

Exposure to hexavalent chromium causes various adverse effects including deep skin ulcerations and allergic dermatitis. Because of many potential intracellular targets for hexavalent chromium toxicity, its mechanisms of action are not entirely understood. To investigate the role of the cytoskeleton and mitochondria in this process, primary human dermal fibroblasts were exposed to various concentrations of potassium chromate for 24 h. The followed markers included cell motility, cytoskeletal organization, oxidative stress, mitochondrial activity and activation of the apoptotic cascade. Potassium chromate (1.5-45 microM) induced time- and concentration-dependent cell shrinkage, reorganization of cytoskeleton and loss of motile activity in fibroblasts. In some cells this was followed by membrane blebbing. Dynamic changes in cell morphology were accompanied with the loss of mitochondrial membrane potential, increased oxidative stress and release of cytochrome c. Apoptosis was confirmed by detection of activated caspase-3 and nuclear fragmentation. The results indicate that in fibroblasts hexavalent chromium-induced damage to cytoskeleton and mitochondria might occur concurrently at relatively early stages of exposure. Furthermore, alterations of these targets seem to activate mitochondria-dependent and- independent apoptosis.
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PMID:Hexavalent chromium disrupts the actin cytoskeleton and induces mitochondria-dependent apoptosis in human dermal fibroblasts. 1590 74

Zinc is an important cellular antioxidant. We investigated its role in chromium-induced oxidative stress and apoptosis in human tumor cell line Hep-2. The measured parameters included intracellular labile zinc content (Zinquin-E fluorescence), cell viability (WST-1 assay), oxidative stress (spectrophotometry), mitochondrial potential (flow cytometry), caspase-3 activity, and PARP cleavage (immunofluorescence). We found that Hep-2 cells contain abundant labile zinc stores that may be depleted by the ionophore TPEN or increased by external zinc supplementation. Chromium (VI)-induced cytotoxicity and apoptosis were enhanced in zinc-depleted cells after 24 h, in particular at chromium (VI) concentrations of 50 and 150 micromol/l. On the other hand, elevated levels of labile zinc were able to protect against apoptosis induced by 10 micromol/l chromium (VI) but at higher chromium (VI) concentrations (50 and 150 micromol/l) acted synergistically, significantly enhancing oxidative stress and the course of apoptosis, possibly through oxidative stress and mitochondrial damage.
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PMID:Zinc has ambiguous effects on chromium (VI)-induced oxidative stress and apoptosis. 1596 74


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