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)

Dolichyl monophosphate (Dol-P) is involved in the attachment of carbohydrate chains to proteins in the formation of N-linked glycoprotein. We found that this compound induces apoptosis in human leukemia U937 cells. During this apoptotic execution, the increase of plasma membrane fluidity (5-20 min), reduction in mitochondrial transmembrane potential (delta psi m) and translocation of apoptosis-inducing factor (1-3 hr), caspase-3-like protease activation (2-4 hr), chromatin condensation and DNA ladder formation (3-4 hr) were observed successively. In this study, we examined mitochondrial morphological changes by electron microscopy and delta psi m by JC-1 from immediately after treatment of Dol-P. After 5 min of treatment, we observed clearly that mitochondrial cristae began to be disrupted ultrastructurally and almost all the cristae were disintegrated after 1 hr of treatment. The delta psi m of Dol-P treated cells was reduced to 34% as compared with that of control cells immediately after treatment and was quartered within 1 hr. The reduction in delta psi m was not inhibited by cyclosporin A, N-acetyl-L-cysteine and vitamin E. These results indicate that mitochondrial disruption is one of the first triggering events of Dol-P-induced apoptosis.
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PMID:Disruption of mitochondria is an early event during dolichyl monophosphate-induced apoptosis in U937 cells. 1202 7

Neuronal apoptosis is one of the pathological features of Alzheimer's disease (AD). Morphological pathology reveals that neuronal apoptosis is associated with senile plaques containing amyloid-beta peptide (Abeta) in AD brains. Reactive oxygen species (ROS) has been proposed to be involved in the apoptotic mechanism of Abeta-mediated neurotoxicity. In the present study, using a rat pheochromocytoma (PC12) cell line, we investigated the effect of Pycnogenol (PYC), a potent antioxidant and ROS scavenger, on Abeta(25-35)-induced apoptosis and ROS generation. We used vitamin E, a known antioxidant agent, to verify the effect of PYC. Abeta(25-35)-induced apoptosis in PC12 cells was demonstrated by: (1) a dose-dependent loss of cell viability; (2) a time- and dose-dependent increase in the apoptotic cells; (3) an induction of DNA fragmentation; and (4) an increase in caspase-3 activity and cleavage of poly (ADP-ribose) polymerase (PARP). Our data showed that a significant increase in ROS formation preceded apoptotic events after PC12 cells were exposed to Abeta(25-35). We further found that PYC not only suppressed the generation of ROS but also attenuated caspase-3 activation, DNA fragmentation, PARP cleavage, and eventually protected against Abeta-induced apoptosis. Vitamin E also suppressed cell death and caspase-3 activation induced by Abeta(25-35). Taken together, these results suggest that ROS may be involved in Abeta-induced apoptosis in PC12 cells. They further suggest that PYC can reduce apoptosis, possibly by decreasing free radical generation in PC12 cells.
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PMID:Pycnogenol protects neurons from amyloid-beta peptide-induced apoptosis. 1211 51

We showed previously that homocysteine thiolactone (HcyT) is a potent inducer of apoptosis in HL-60 cells. In the present study, the role of some radical scavengers (N-acetylcysteine, vitamin C, vitamin E and folate) on the reduction of HcyT-induced apoptosis was investigated. Preincubation of HcyT-treated HL-60 cells with vitamin C (Vit C; 100 micro mol/L) or vitamin E (Vit E; 100 micro mol/L) for 2 h significantly reduced the proportion of apoptotic cells with hypodiploid DNA contents or with membrane phosphatidylserine exposure, and attenuated the apoptotic DNA fragmentation. Preincubation of cells with N-acetylcysteine (NAC; 5 mmol/L) for 2 h significantly reduced HcyT-promoted apoptosis measured by membrane phosphatidylserine exposure only. The reduction of HcyT-induced apoptosis by NAC, Vit C or Vit E occurred simultaneously with a significant decrease in intracellular H(2)O(2) levels and reduced caspase-3 enzymatic activity. In contrast, folate had no H(2)O(2) scavenging capacity and did not suppress caspase-3 activity 6 h after HcyT treatment, although folate exhibited antioxidant behavior toward superoxide anions, hydroxyl radicals and peroxynitrite. Preincubation of cells with folate (10 micro mol/L) for 3 d did not affect the extent of HcyT-promoted apoptotic damage. Taken together, our findings suggest that antioxidant pretreatment with NAC, Vit C or Vit E exerts more beneficial effects than folate on reducing apoptotic cell damage induced by homocysteine thiolactone.
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PMID:N-Acetylcysteine, vitamin C and vitamin E diminish homocysteine thiolactone-induced apoptosis in human promyeloid HL-60 cells. 1216 54

Airway epithelial cells (AEC) contain both pro- and anti-apoptotic factors but little is known about mechanisms regulating apoptosis of these cells. In this study we have examined the localization of pro-caspase-3 and Zn(2+), a cellular regulator of pro-caspase-3, in primary sheep and human AEC. Zn(2+) was concentrated in both cytoplasmic vesicles and ciliary basal bodies, in the vicinity of both pro-caspase-3 and the antioxidant Cu/Zn superoxide dismutase (Cu/Zn SOD). Depletion of intracellular Zn(2+) in sheep AEC, using the membrane permeant Zn(2+) chelator TPEN, increased lipid peroxidation in the apical cell membranes (as assessed by immunofluorescence with anti-hydroxynonenal) as well as increasing activated pro-caspase-3 and apoptosis. There were smaller increases in caspase-2 and -6 but not other caspases. Activation of caspase-3 in TPEN-treated AEC was inhibited strongly by N-acetylcysteine and partially by vitamin C and vitamin E. These findings suggest that cytoplasmic pro-caspase-3 is positioned near the lumenal surface of AEC where it is under the influence of Zn(2+) and other anti-oxidants.
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PMID:Involvement of redox events in caspase activation in zinc-depleted airway epithelial cells. 1235 64

Standard Ginkgo biloba leaf extract (EGb 761) has been known to have neuroprotective effects ranging from molecular and cellular, to animal and human studies, however, the cellular and molecular mechanisms remain unclear. Using PC 12 cells, a well-established model for studying neuroprotection, we have determined the mechanism of action of EGb 761 on cell survival following apoptosis induced by serum-deprivation or treatment with staurosporine (STS). Our results show that EGb 761 treatments of PC12 cells are able to prevent serum deprivation- and STS-induced mitochondrial damage, attenuate release of cytochrome c and DNA fragmentation. EGb 761, but not vitamin E. inhibited STS-induced activation of the caspase-3 enzyme. Two of the EGb 761 components, bilobalide B and ginkgolide C show more significant inhibition than the EGb 761 extract. Furthermore, DNA microarray assay results indicate that transcription of multiple apoptosis-related genes is either up- or down-regulated in cells treated with EGb 761. These results suggest that inhibition of apoptotic machinery may, at least in part, mediate multiple neuroprotective effects of EGb 761, and that EGb 761 and vitamin E act on different molecular paths to provide neuroprotection.
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PMID:Anti-apoptotic properties of Ginkgo biloba extract EGb 761 in differentiated PC12 cells. 1239 82

Exposure of cerebellar granule cells (CGCs) to 1-methyl-4-phenylpyridinium (MPP+) results in apoptotic cell death, which is markedly attenuated by co-treatment of CGCs with the radical scavenger vitamin E. Analysis of free radical production and mitochondrial transmembrane potential (DeltaPsim), using specific fluorescent probes, showed that MPP+ mediates early radical oxygen species (ROS) production without a loss of DeltaPsim. Exposure to MPP+ also produces an early increase in Bad dephosphorylation and translocation of Bax to the mitochondria. These events are accompanied by cytochrome c release from mitochondria to cytosol, which is followed by caspase 3 activation. Exposure of the neurons to vitamin E maintains Bad phosphorylation and attenuates Bax translocation, inhibiting cytochrome c release and caspase activation. MPP+-mediated cytochrome c release is also prevented by allopurinol, suggesting the participation of xanthine oxidase in the process. Our results indicate that free radicals play an active role in the MPP+-induced early events that culminate with cell death.
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PMID:Vitamin E blocks early events induced by 1-methyl-4-phenylpyridinium (MPP+) in cerebellar granule cells. 1255 93

Recent reports indicate a broad spectrum of antileukemic activity for arsenic trioxide (As(2)O(3)) due to its ability to induce apoptosis via intracellular production of reactive oxygen species (ROS). Despite its potent apoptotic mechanism, As(2)O(3) is not equally effective in all leukemic cells, which has prompted a search for agents enhancing As(2)O(3) efficacy. Recently, evidence has been gathered that the polyunsaturated fatty acid docosahexaenoic acid (DHA) may sensitize tumor cells to ROS-inducing anticancer agents. The aim of our investigation was to evaluate whether DHA enhances As(2)O(3)-mediated apoptosis in As(2)O(3)-resistant HL-60 cells. While 1 microM As(2)O(3) or 25 microM DHA reduced cell viability to 85.8% +/- 2.9% and 69.2% +/- 3.6%, combined treatment with As(2)O(3) and DHA reduced viability to 13.0% +/- 9.9% with a concomitant increase of apoptosis. Apoptotic cell death was preceded by collapse of the mitochondrial membrane potential, increased expression of proapoptotic B-cell lymphoma protein-2-associated X protein (Bax), and caspase-3 activation. Importantly, the combined effect of As(2)O(3) and DHA was associated with increased production of intracellular ROS and toxic lipid peroxidation products and was abolished by the antioxidant vitamin E or when oleic acid (a nonperoxidizable fatty acid) was used in place of DHA. Intracellular ROS and toxic lipid peroxidation products most likely constitute the key mediators contributing to the combined effect of As(2)O(3) and DHA. Our data provide the first evidence that DHA may help to extend the therapeutic spectrum of As(2)O(3) and suggest that the combination of As(2)O(3) and DHA could be more broadly applied in leukemia therapy.
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PMID:Docosahexaenoic acid enhances arsenic trioxide-mediated apoptosis in arsenic trioxide-resistant HL-60 cells. 1260 32

alpha-Tocopheryl succinate (alpha-TOS) is a semisynthetic vitamin E analogue with high pro-apoptotic and anti-neoplastic activity [Weber, T et al. (2002) Clin. Cancer Res. 8, 863-869]. Previous studies suggested that it acts through destabilization of subcellular organelles, including mitochondria, but compelling evidence is missing. Cells treated with alpha-TOS showed altered mitochondrial structure, generation of free radicals, activation of the sphingomyelin cycle, relocalization of cytochrome c and Smac/Diablo, and activation of multiple caspases. A pan-caspase inhibitor suppressed caspase-3 and -6 activation and phosphatidyl serine externalization, but not decrease of mitochondrial membrane potential or generation of radicals. For alpha-TOS, but not Fas or TRAIL, apoptosis was suppressed by caspase-9 inhibition, while TRAIL- and Fas-resistant cells overexpressing cFLIP or CrmA were susceptible to alpha-TOS. The central role of mitochondria was confirmed by resistance of mtDNA-deficient cells to alpha-TOS, by regulation of alpha-TOS apoptosis by Bcl-2 family members, and by anti-apoptotic activity of mitochondrially targeted radical scavengers. Co-treatment with alpha-TOS and anti-Fas IgM showed their cooperative effect, probably by signaling via different, convergent pathways. These data provide an insight into the molecular mechanism, by which alpha-TOS kills malignant cells, and advocate its testing as a potential anticancer agent or adjuvant.
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PMID:Mitochondria play a central role in apoptosis induced by alpha-tocopheryl succinate, an agent with antineoplastic activity: comparison with receptor-mediated pro-apoptotic signaling. 1268 Jul 82

Hyperthermia-induced apoptosis and its enhancement in the presence of a temperature-dependent free radical initiator, 2,2'-azobis (2-aminopropane) dihydrochloride (AAPH) were examined in human uterine cervical cancer cell lines, CaSki and HeLa. When both cell lines were treated with hyperthermia at 44 degrees C for 60 min, minimal apoptosis was observed. When combined with nontoxic AAPH (50mM), significant enhancement of apoptosis was observed, where the initial rate of free radical formation was about twice as high than that at 37 degrees C. Augmentation of the growth delay, lipid peroxidation (LPO), activation of caspase-3 and increase in [Ca2+]i were also observed after the combined treatment. A water-soluble vitamin E, Trolox, blocked the increase in [Ca2+]i and an intracellular Ca2+ chelator, BAPTA-AM, prevented the DNA fragmentation induced by the combination. Cytochrome c release was also revealed by fluorescence microscopy. However, no significant change in mitochondrial membrane potential and expression of Bax and Bcl-2 was observed. A slight increase in Fas expression was observed only in CaSki cells after the combined treatment. These results indicate that hyperthermia and AAPH induce enhanced apoptosis and subsequent cell killing via two pathways; a pathway dependenton increase in LPO and [Ca2+]i, and a pathway associated with cytochrome c release and subsequent caspase activation without changes of mitochondrial membrane potential and Bax/Bcl-2 expression in these cell lines. Since it is known that cancer cells are generally resistant to physical and chemical stress-induced apoptosis, free radical generators like AAPH appear to be a useful thermosensitizer for hyperthermic cancer therapy.
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PMID:A free radical initiator, 2,2'-azobis (2-aminopropane) dihydrochloride enhances hyperthermia-induced apoptosis in human uterine cervical cancer cell lines. 1286 90

The vitamin E family of compounds is divided into two subgroups, tocopherols and tocotrienols. However, tocotrienols display more potent apoptotic activity in mammary cancer cells. Although the mechanism(s) mediating tocotrienol-induced apoptosis is presently unknown, apoptosis is carried out by activation of initiator caspases (caspase-8 or -9) that subsequently activate effector caspases (caspase-3, -6, or -7). Studies were conducted to determine whether tocotrienol-induced apoptosis is mediated by activation of the caspase-8 and/or caspase-9 pathway. Highly malignant +SA mouse mammary epithelial cells were grown in culture and maintained on serum-free media. Treatment with tocotrienol-rich-fraction of palm oil (TRF) and g-tocotrienol, but not a-tocopherol, induced a dose-dependent decrease in +SA cell viability. TRF- and g-tocotrienol-induced cell death resulted from apoptosis, as determined by DNA fragmentation and positive TUNEL assay staining. Additional studies showed that treatment with 50 mM TRF or 20 mM g-tocotrienol increased intracellular activity and levels of processed caspase-8 and -3 but not caspase-9. Furthermore, treatment with specific caspase-8 or -3 inhibitors, but not caspase-9 inhibitor, completely blocked the tocotrienol-induced apoptosis in +SA cells. These findings demonstrate that tocotrienol-induced apoptosis in +SA mammary cancer cells is mediated through activation of the caspase-8 signaling pathway and is independent of caspase-9 activation.
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PMID:Role of caspase-8 activation in mediating vitamin E-induced apoptosis in murine mammary cancer cells. 1288 Oct 19


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