Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although pectenotoxin-2 (PTX-2) is known to modify the actin cytoskeleton, very little is known about its apoptosis mechanism. In this study, we investigated whether PTX-2 induces apoptotic effects through suppression of the NF-kappaB signaling pathway in several leukemia cell types. PTX-2 significantly induced growth inhibition and apoptosis in a dose-dependent manner. Treatment with PTX-2 also significantly increased caspase-3 activity and poly (ADP-ribose) polymerase (PARP) cleavage, however caspase-3 inhibitor z-DEVD-fmk significantly inhibited PTX-2-induced cell death. These data suggest that the activation of caspase-3 is associated with PTX-2-induced apoptosis. NF-kappaB has also been shown to inhibit apoptosis in response to chemotherapeutic agents. As examined by the DNA-binding of NF-kappaB activation, we found that PTX-2 suppressed constitutive NF-kappaB activation and determined by p65 and p50 nuclear translocation, and IkappaBalpha degradation through dephosphorylation of Akt. Attenuation of constitutive NF-kappaB activity by pretreatment with pyrrolidine dithiocarbamate (PDTC), an NF-kappaB nuclear translocation inhibitor, induced significantly apoptosis in the presence of PTX-2. In addition, treatment of PTX-2 down-regulated NF-kappaB-dependent gene expression, Cox-2, IAP-1, IAP-2 and XIAP, at the transcriptional and translational level. Taken together, these results suggest that anti-cancer activities induced by PTX-2 may be mediated in part through suppression of constitutive NF-kappaB activity.
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PMID:Pectenotoxin-2 abolishes constitutively activated NF-kappaB, leading to suppression of NF-kappaB related gene products and potentiation of apoptosis. 1860 10

Because the phosphatidylinositol-3-kinase-AKT pathway is emerging as an important regulator of tumor cell survival, inhibitors of this pathway have enormous potential in cancer treatment. A specific inhibitor of AKT, [d-3-deoxy-2-O-methyl-myo-inositol-1-[(R)-2-methoxy-3-(octadecyloxy)propyl hydrogen phosphate]] (SH-5) has been recently synthesized, but little is known about its effects on cytokine signaling. We found that SH-5 potentiated the apoptosis induced by tumor necrosis factor (TNF), as indicated by intracellular esterase staining, annexin V staining, and caspase-3 activation. This effect of SH-5 correlated with downregulation of various gene products that mediate cell survival, proliferation, metastasis, and invasion, all known to be regulated by NF-kappaB. SH-5 also blocked NF-kappaB activation induced by TNF-alpha, lipopolysaccharide, phorbol ester, and cigarette smoke but not that activated by hydrogen peroxide and RANK ligand, indicating differential requirement of AKT. Inhibition of NF-kappaB correlated with abrogation of phosphorylation and degradation of IkappaBalpha through the inhibition of activation of IkappaBalpha kinase (IKK). This led to suppression of the phosphorylation and translocation of p65 and also of NF-kappaB reporter activity induced by TNFR1, TRADD, TRAF2, NIK, and IKKbeta but not that induced by p65 transfection. Thus, our results clearly demonstrate that inhibition of AKT leads to potentiation of apoptosis through modulation of NF-kappaB signaling.
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PMID:SH-5, an AKT inhibitor potentiates apoptosis and inhibits invasion through the suppression of anti-apoptotic, proliferative and metastatic gene products regulated by IkappaBalpha kinase activation. 1860 97

Osteoarthritis is an inflammatory disease of load-bearing synovial joints that is currently treated with drugs that exhibit numerous side effects and are only temporarily effective on pain, the main symptom of the disease. Consequently, there is an acute need for novel, safe and more effective chemotherapeutic agents for the treatment of osteoarthritis and related arthritic diseases. Resveratrol is a phytoalexin stilbene produced naturally by plants including red grapes, peanuts and various berries. Recent research in various cell models has demonstrated that resveratrol is safe and has potent anti-inflammatory properties. However, its potential for treating arthritic conditions has not been explored. In this study we provide experimental evidence that resveratrol inhibits the expression of VEGF, MMP-3, MMP-9 and COX-2 in human articular chondrocytes stimulated with the pro-inflammatory cytokine IL-1beta. Since these gene products are regulated by the transcription factor NF-kappaB, we investigated the effects of resveratrol on IL-1beta-induced NF-kappaB signaling pathway. Resveratrol, like N-Ac-Leu-Leu-norleucinal (ALLN) suppressed IL-1beta-induced proteasome function and the degradation of IkappaBalpha (an inhibitor of NF-kappaB) without affecting IkappaBalpha kinase activation, IkappaBalpha-phosphorylation or IkappaBalpha-ubiquitination which suppressed nuclear translocation of the p65 subunit of NF-kappaB and its phosphorylation. Furthermore, we observed that resveratrol as well as ALLN inhibited IL-1beta-induced apoptosis, caspase-3 activation and PARP cleavage in human articular chondrocytes. In summary, our results suggest that resveratrol suppresses apoptosis and inflammatory signaling through its actions on the NF-kappaB pathway in human chondrocytes. We propose that resveratrol should be explored further for the prophylactic treatment of osteoarthritis in humans and companion animals.
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PMID:Resveratrol suppresses interleukin-1beta-induced inflammatory signaling and apoptosis in human articular chondrocytes: potential for use as a novel nutraceutical for the treatment of osteoarthritis. 1860 98

Adult T-cell leukemia (ATL) is a fatal malignancy of T lymphocytes caused by human T-cell leukemia virus type 1 (HTLV-1) infection and remains incurable. Carotenoids are a family of natural pigments and have several biological functions. Among carotenoids, fucoxanthin is known to have antitumorigenic activity, but the precise mechanism of action is not elucidated. We evaluated the anti-ATL effects of fucoxanthin and its metabolite, fucoxanthinol. Both carotenoids inhibited cell viability of HTLV-1-infected T-cell lines and ATL cells, and fucoxanthinol was approximately twice more potent than fucoxanthin. In contrast, other carotenoids, beta-carotene and astaxanthin, had mild inhibitory effects on HTLV-1-infected T-cell lines. Importantly, uninfected cell lines and normal peripheral blood mononuclear cells were resistant to fucoxanthin and fucoxanthinol. Both carotenoids induced cell cycle arrest during G(1) phase by reducing the expression of cyclin D1, cyclin D2, CDK4 and CDK6, and inducing the expression of GADD45alpha, and induced apoptosis by reducing the expression of Bcl-2, XIAP, cIAP2 and survivin. The induced apoptosis was associated with activation of caspase-3, -8 and -9. Fucoxanthin and fucoxanthinol also suppressed IkappaBalpha phosphorylation and JunD expression, resulting in inactivation of nuclear factor-kappaB and activator protein-1. Mice with severe combined immunodeficiency harboring tumors induced by inoculation of HTLV-1-infected T cells responded to treatment with fucoxanthinol with suppression of tumor growth, showed extensive tissue distribution of fucoxanthinol, and the presence of therapeutically effective serum concentrations of fucoxanthinol. Our preclinical data suggest that fucoxanthin and fucoxanthinol could be potentially useful therapeutic agents for patients with ATL.
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PMID:Anti-adult T-cell leukemia effects of brown algae fucoxanthin and its deacetylated product, fucoxanthinol. 1879 63

Sulforaphane (SFN) is a biologically active compound extracted from cruciferous vegetables, and possessing potent anti-cancer and anti-inflammatory activities. Here, we show that tumor necrosis factor-alpha (TNF-alpha), in combination with a sub-toxic dose of SFN, significantly triggered apoptosis in TNF-alpha-resistant leukemia cells (THP-1, HL60, U937, and K562), which was associated with caspase activity and poly (ADP-ribose)-polymerase cleavage. We also report that SFN non-specifically inhibited TNF-alpha-induced NF-kappaB activation through the inhibition of IkappaBalpha phosphorylation, IkappaBalpha degradation, and p65 nuclear translocation. This inhibition correlated with the suppression of NF-kappaB-dependent genes involved in anti-apoptosis (IAP-1, IAP-2, XIAP, Bcl-2, and Bcl-xL), cell proliferation (c-Myc, COX-2, and cyclin D1), and metastasis (VEGF and MMP-9). These effects suggest that SFN inhibits TNF-alpha-induced NF-kappaB activation through the suppression of IkappaBalpha degradation, leading to reduced expression of NF-kappaB-regulated gene products. Combined treatment with SFN and TNF-alpha was also accompanied by the generation of reactive oxygen species (ROS). Pre-treatment with N-acetyl-l-cysteine significantly attenuated the combined treatment-induced ROS generation and caspase-3-dependent apoptosis, implying the involvement of ROS in this type of cell death. In conclusion, the results of the present study indicate that SFN suppresses TNF-alpha-induced NF-kappaB activity and induces apoptosis through activation of ROS-dependent caspase-3.
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PMID:Sulforaphane suppresses TNF-alpha-mediated activation of NF-kappaB and induces apoptosis through activation of reactive oxygen species-dependent caspase-3. 1895 68

Effective treatment of malignant melanoma with the tumor-selective death ligand tumor necrosis-related apoptosis-inducing ligand (TRAIL) is curtailed by the fact that many melanoma cell lines are a priori resistant against TRAIL-induced apoptosis. By investigating 18 melanoma cell lines, we show that TRAIL susceptibility is completely independent of the tumor progression stage but can be positively stimulated by co-exposure to a sublethal ultraviolet B light (UVB) dose, providing an excellent tool to study the mechanism underlying TRAIL resistance. TRAIL resistance could be linked to the ratio of x-linked inhibitor of apoptosis proteins (xIAP) and caspase-3 levels within the cell. UVB-induced sensitization coincides with enhanced xIAP degradation, allowing full caspase-3 processing and activation. It is also accompanied by concomitant IkappaBalpha degradation, resulting in nuclear factor-kappaB (NF-kappaB)-dependent transcriptional repression of xIAP. Loss of xIAP in turn was reduced upon overexpression of an IkappaBalpha super-repressor, thus NF-kappaB activation seems to be responsible for differential regulation of xIAP and consequently determines TRAIL susceptibility. As xIAP-mediated blockade of apoptosis seems to be the dominant cause of TRAIL resistance of all melanoma cell lines investigated here, our data suggest that direct chemical xIAP inhibition or combination treatment with DNA-damaging agents may offer new therapeutic strategies to generally sensitize melanoma toward TRAIL-induced apoptosis.
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PMID:Sensitization of melanoma cells to TRAIL by UVB-induced and NF-kappaB-mediated downregulation of xIAP. 1897 16

Recent reports implicate poly(ADP-ribose) polymerase-1 (PARP-1) in the activation of nuclear factor kappaB (NF-kappaB). We investigated the role of PARP-1 in the NF-kappaB signalling cascade induced by ionizing radiation (IR). AG14361, a potent PARP-1 inhibitor, was used in two breast cancer cell lines expressing different levels of constitutively activated NF-kappaB, as well as mouse embryonic fibroblasts (MEFs) proficient or deficient for PARP-1 or NF-kappaB p65. In the breast cancer cell lines, AG14361 had no effect on IR-induced degradation of IkappaBalpha or nuclear translocation of p50 or p65. However, AG14361 inhibited IR-induced NF-kappaB-dependent transcription of a luciferase reporter gene. Similarly, in PARP-1(-/-) MEFs, IR-induced nuclear translocation of p50 and p65 was normal, but kappaB binding and transcriptional activation did not occur. AG14361 sensitized both breast cancer cell lines to IR-induced cell killing, inhibited IR-induced XIAP expression and increased caspase-3 activity. However, AG14361 failed to increase IR-induced caspase activity when p65 was knocked down by siRNA. Consistent with this, AG14361 sensitized p65(+/+) but not p65(-/-) MEFs to IR. We conclude that PARP-1 activity is essential in the upstream regulation of IR-induced NF-kappaB activation. These data indicate that potentiation of IR-induced cytotoxicity by AG14361 is mediated solely by inhibition of NF-kappaB activation.
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PMID:Ionizing radiation-induced NF-kappaB activation requires PARP-1 function to confer radioresistance. 1906 Sep 26

NF-kappaB activation is exaggerated in neonatal organisms after oxidant and inflammatory insults, but the reason for this and the downstream effects are unclear. We hypothesized that specific phosphorylation patterns of IkappaBalpha could account for differences in NF-kappaB activation in hyperoxia-exposed fetal and adult lung fibroblasts. After exposure to hyperoxia (>95% O(2)), nuclear NF-kappaB binding increased in fetal, but not adult, lung fibroblasts. Unique to fetal cells, phosphorylation of IkappaBalpha on tyrosine 42, rather than serine 32/36 as seen in TNF-alpha-exposed cells, preceded NF-kappaB nuclear translocation. In fetal cells stably transfected with an NF-kappaB-driven luciferase reporter, hyperoxia significantly suppressed reporter activity, in contrast to increased reporter activity after TNF-alpha incubation. Targeted gene profiling analysis showed that hyperoxia resulted in decreased expression of multiple genes, including proapoptotic factors. Transfection with a dominant-negative IkappaBalpha (Y42F), which cannot be phosphorylated on tyrosine 42, resulted in upregulation of multiple proapoptotic genes. In support of this finding, caspase-3 activity and DNA laddering were specifically increased in fetal lung fibroblasts expressing Y42F after exposure to hyperoxia. These data demonstrate a unique pathway of NF-kappaB activation in fetal lung fibroblasts after exposure to hyperoxia, whereby these cells are protected against apoptosis. Activation of this pathway in fetal cells may prevent the normal pattern of fibroblast apoptosis necessary for normal lung development, resulting in aberrant lung morphology in vivo.
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PMID:Hyperoxia-induced NF-kappaB activation occurs via a maturationally sensitive atypical pathway. 1907 56

Anesthetic preconditioning (APC), defined as brief exposure to inhalational anesthetics before cardiac ischemia-reperfusion (I/R), limits injury in both animal models and in humans. APC can result in the production of reactive oxygen species (ROS), and prior work has shown that APC can modify activation of NF-kappaB during I/R, with consequent reduction in the expression of inflammatory mediators. However, the role of NF-kappaB activation before I/R is unknown. Therefore, these experiments tested the hypothesis that APC-induced ROS results in activation of NF-kappaB before I/R, with consequent increased expression of antiapoptotic proteins such as Bcl-2 and decreased apoptosis. Experiments utilized an established perfused heart rat model of sevoflurane APC and I/R. The role of NF-kappaB was defined by a novel method of transient inhibition of the regulatory kinase IKK using the reversible inhibitor SC-514. In addition to functional measures of left ventricular developed and end-diastolic pressure, phosphorylation of IkappaBalpha and activation of NF-kappaB were measured along with cytosolic protein content of Bcl-2, release of cytochrome c, and degradation of caspase-3. APC resulted in ROS-dependent phosphorylation of IkappaBalpha and activation of NF-kappaB before I/R. APC also increased the expression of Bcl-2 before I/R. In addition to functional protection following I/R, APC resulted in lower release of cytochrome c and caspase-3 degradation. These protective effects of APC were abolished by transient inhibition of IkappaBalpha phosphorylation and NF-kappaB activation by SC-514 followed by washout. ROS-dependent activation of NF-kappaB by APC before I/R is a critical element in the protective effect of APC. APC reduces apoptosis and functional impairment by increasing Bcl-2 expression before I/R. Interventions that increase NF-kappaB activation before I/R should protect hearts from I/R injury.
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PMID:Activation of NF-kappaB is a critical element in the antiapoptotic effect of anesthetic preconditioning. 1930 43

Because tumor necrosis factor-alpha (TNF-alpha) is well-known to induce inflammatory responses, thus its clinical use is limited in cancer treatment. Rosmarinic acid (RA), a naturally occurring polyphenol flavonoid, has been reported to inhibit TNF-alpha-induced NF-kappaB activation in human dermal fibroblasts. However, the precise mechanisms of RA have not been well elucidated in TNF-alpha-mediated anti-cancer therapy. In this study, we found that RA treatment significantly sensitizes TNF-alpha-induced apoptosis in human leukemia U937 cells through the suppression of nuclear transcription factor-kappaB (NF-kappaB) and reactive oxygen species (ROS). Activation of caspases in response to TNF-alpha was markedly increased by RA treatment. However, pretreatment with the caspase-3 inhibitor, z-DEVD-fmk, was capable of significantly restoring cell viability in response to combined treatment. RA also suppressed NF-kappaB activation through inhibition of phosphorylation and degradation of IkappaBalpha, and nuclear translocation of p50 and p65. This inhibition was correlated with suppression of NF-kappaB-dependent anti-apoptotic proteins (IAP-1, IAP-2, and XIAP). RA treatment also normalized TNF-alpha-induced ROS generation. Additionally, ectopic Bcl-2 expressing U937 reversed combined treatment-induced cell death, cytochrome c release into cytosol, and collapse of mitochondrial potential. These results demonstrated that RA inhibits TNF-alpha-induced ROS generation and NF-kappaB activation, and enhances TNF-alpha-induced apoptosis.
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PMID:Rosmarinic acid sensitizes cell death through suppression of TNF-alpha-induced NF-kappaB activation and ROS generation in human leukemia U937 cells. 1961 38


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