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)

PML nuclear bodies (NBs) are nuclear matrix-associated structures altered by viruses and oncogenes. We show here that PML overexpression induces rapid cell death, independent of de novo transcription and cell cycling. PML death involves cytoplasmic features of apoptosis in the absence of caspase-3 activation, and caspase inhibitors such as zVAD accelerate PML death. zVAD also accelerates interferon (IFN)-induced death, suggesting that PML contributes to IFN-induced apoptosis. The death effector BAX and the cdk inhibitor p27KIP1 are novel NB-associated proteins recruited by PML to these nuclear domains, whereas the acute promyelocytic leukaemia (APL) PML/RAR alpha oncoprotein delocalizes them. Arsenic enhances targeting of PML, BAX and p27KIP1 to NBs and synergizes with PML and IFN to induce cell death. Thus, cell death susceptibility correlates with NB recruitment of NB proteins. These findings reveal a novel cell death pathway that neither requires nor induces caspase-3 activation, and suggest that NBs participate in the control of cell survival.
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PMID:PML induces a novel caspase-independent death process. 980 33

Metallothionein (MT) is a low-molecular-weight, sulfhydryl-rich, metal-binding protein that can protect against the toxicity of cadmium, mercury, and copper. However, the role of MT in arsenic (As)-induced toxicity is less certain. To better define the ability of MT to modify As toxicity, MT-I/II knockout (MT-null) mice and the corresponding wild-type mice (WT) were exposed to arsenite [As(III)] or arsenate [As(V)] either through the drinking water for 48 weeks, or through repeated sc injections (5 days/week) for 15 weeks. Chronic As exposure increased tissue MT concentrations (2-5-fold) in the WT but not in MT-null mice. Arsenic by both routes produced damage to the liver (fatty infiltration, inflammation, and focal necrosis) and kidney (tubular cell vacuolization, inflammatory cell infiltration, and interstitial fibrosis) in both MT-null and WT mice. However, in MT-null mice, the pathological lesions were more frequent and severe when compared to WT mice. This was confirmed biochemically, in that, at the higher oral doses of As, blood urea nitrogen (BUN) levels were increased more in MT-null mice (60%) than in WT mice (30%). Chronic As exposures produced 2-10 fold elevation of serum interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha levels, with greater increases seen by repeated injections than by oral exposure, and again, MT-null mice had higher serum cytokines than WT mice after As exposure. Repeated As injections also decreased hepatic glutathione (GSH) by 35%, but GSH-peroxidase and GSH-reductase were minimally affected. MT-null mice were more sensitive than WT mice to the effect of GSH depletion by As(V). Hepatic caspase-3 activity was increased (2-3-fold) in both WT and MT-null mice, indicative of apoptotic cell death. In summary, chronic inorganic As exposure produced injuries to multiple organs, and MT-null mice are generally more susceptible than WT mice to As-induced toxicity regardless of route of exposure, suggesting that MT could be a cellular factor in protecting against chronic As toxicity.
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PMID:Metallothionein-I/II null mice are more sensitive than wild-type mice to the hepatotoxic and nephrotoxic effects of chronic oral or injected inorganic arsenicals. 1082 79

Arsenic can induce apoptosis and is an efficient drug for the treatment of acute promyelocytic leukemia. Currently, clinical studies are investigating arsenic as a therapeutic agent for a variety of malignancies. In this study, Hodgkin/Reed-Sternberg (HRS) cell lines served as model systems to characterize the role of nuclear factor-kappaB (NF-kappaB) in arsenic-induced apoptosis. Arsenic rapidly down-regulated constitutive IkappaB kinase (IKK) as well as NF-kappaB activity and induced apoptosis in HRS cell lines containing functional IkappaB proteins. In these cell lines, apoptosis was blocked by inhibition of caspase-8 and caspase-3-like activity. Furthermore, arsenic treatment down-regulated NF-kappaB target genes, including tumor necrosis factor-alphareceptor-associated factor 1 (TRAF1), c-IAP2, interleukin-13 (IL-13), and CCR7. In contrast, cell lines with mutated, functionally inactive IkappaB proteins or with a weak constitutive IKK/NF-kappaB activity showed no alteration of the NF-kappaB activity and were resistant to arsenic-induced apoptosis. A direct role of the NF-kappaB pathway in arsenic-induced apoptosis is shown by transient overexpression of NF-kappaB-p65 in L540Cy HRS cells, which protected the cells from arsenic-induced apoptosis. In addition, treatment of NOD/SCID mice with arsenic trioxide induced a dramatic reduction of xenotransplanted L540Cy Hodgkin tumors concomitant with NF-kappaB inhibition. We conclude that inhibition of NF-kappaB contributes to arsenic-induced apoptosis. Furthermore, pharmacologic inhibition of the IKK/NF-kappaB activity might be a powerful treatment option for Hodgkin lymphoma.
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PMID:Inhibition of NF-kappaB essentially contributes to arsenic-induced apoptosis. 1267 92

We have previously shown that arsenic trioxide blocks proliferation and induces apoptosis in human pancreatic cancer cells at low, non-toxic concentrations. The mechanisms of the apoptosis was investigated in MiaPaCa2 and PANC-1 cells that have been previously shown to be responsive to arsenic trioxide. The results show the caspase-3, caspase-7, and caspase-9 are all activated by arsenic trioxide, together with cleavage of the downstream caspase-3 target poly ADP ribose polymerase (PARP). Expression of the anti-apoptosis proteins, Bcl-2 and Mcl-1 expression decreased time-dependently while Bax expression increased. These findings indicate that the Bcl family of proteins, the mitochondrial pathway and activation of the caspase cascade are responsible for arsenic-induced apoptosis. Flow cytometric analysis revealed changes of cell cycle distribution from a G0/G1 phase arrest at 24 hours to G2/M phase arrest at 72 hours following arsenic treatment. The sub-G0/G1 cell population of apoptotic cells was increased at these times. Arsenic increased expression of the P21 protein and decreased levels of cyclin A, cyclin B1 and cyclin D1, but expression of CDK2, CDK4, CDK6, and cyclin E were not affected. Arsenic trioxide markedly enhanced the expression of GADD45 and GADD153 in a time-dependent manner. In summary, arsenic trioxide induced apoptosis in pancreatic cancer cells through activating the caspase cascade via the mitochondrial pathway, GADD expression and by modifying cell cycle progress and changes in several cycle-regulating proteins. This old drug may be valuable for treatment of pancreatic cancer.
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PMID:Arsenic trioxide induces apoptosis in pancreatic cancer cells via changes in cell cycle, caspase activation, and GADD expression. 1288 67

These studies explore the molecular effect of arsenicals on MM cells. Freshly isolated cells derived from patients with advanced, chemo-refractory myeloma as well as human myeloma cell lines, ARP-1, RPMI-8226 and H929 were exposed to the organic arsenical melarsoprol and to the inorganic compound AT. Both agents potently induced apoptosis in myeloma cells. Exposure to 1-5 microM AT or melarsoprol for 6 hours suppressed NF-kappa B DNA binding and enhanced of c-Jun kinase (JNK) activity. Arsenic also activated caspase-3 resulting in the cleavage of poly (ADP-ribose) polymerase (PARP) and Fas/TNF alpha related receptor interacting protein (RIP). In contrast to reported observations in acute promyelocytic leukemia, myeloma cell apoptosis was not associated with either the downregulation of Bcl-2 protein or with alterations in the expression of other Bcl-2 family members, Bax, Bak, Bag, and Bcl-xl. This study first shows that arsenic induces apoptotic signaling in MM through the cleavage of TNF alpha related receptor interacting protein (RIP). RIP is a key downstream protein in FasL/ TNF alpha /TRAIL induced apoptosis and a major antiapoptotic adaptor of pathways through NF-kappa B and JNK. RIP has not been previously characterized in myeloma. This study supports the hypothesis that arsenicals share common mediators (RIP, NF-kappa B, PARP, caspase-3) with death receptor induced apoptosis. These studies provide an important insight into the molecular mechanism of AT induced apoptosis and can be used in the development of adjuvant therapy for MM, presently an incurable disease.
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PMID:RIP kinase is involved in arsenic-induced apoptosis in multiple myeloma cells. 1531 84

Apoptosis or programmed cell death (PCD) is a genetically regulated cellular, physiological and biochemical suicidal mechanism that plays a crucial role in the development and defense of homeostasis, in which the cell participates in its own demise via a cascade of molecular interactions. PCD can be modulated by various stimuli including infectious agents or drugs. Arsenic is one among inducible toxic agent that triggers apoptosis via free radical generation. Since the generation of free radicals during the metabolism of arsenic is thought to be involved in arsenic toxicosis, understanding the deleterious effects caused by the ROS that attack the vital molecules like DNA has become important. The present work was conducted to evaluate the regulatory effect exerted by Vitamin C and Vitamin E upon the apoptotic process, which can be assessed by the presence of cells with apoptosis associated DNA breaks and characterize the role of TNF-alpha and caspase-3 in rats intoxicated with arsenic. Male albino rats of wistar strain (120-150 g) were used in this study and are further divided into seven groups. We observed that ascorbate and alpha-tocopherol selectively altered the extent of DNA damage by reducing TNF-alpha level and inhibiting the activation of caspase cascade, from these observations it is strongly believed that the present vitamins supplementation perspective, though observed in animal model, will have sustainable curative value among the already afflicted populations, neutralizing impact on freshly emerging arsenicosis scenario and possible proactive protection to those potentially susceptible to arsenicals exposure.
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PMID:Ascorbic acid and alpha-tocopherol as potent modulators of apoptosis on arsenic induced toxicity in rats. 1573 92

Arsenic is a well established human carcinogen and is ubiquitous in the environment. The present study demonstrates the effect of acute arsenic administration at three different doses in liver and brain of Wistar rats. Sodium arsenite was administered orally at doses of 6.3 mg/kg, 10.5 mg/kg and 12.6 mg/kg of body weight on the basis of a lethal dose 50% (LD50) for 24 hr. After administration of arsenites, liver and brain were analyzed for various parameters of oxidative stress, histopathological changes and caspase-3 activity. Glutathione levels were decreased significantly in the liver at all doses. In liver the following biochemical changes were observed, a significant lipid peroxidation and cytochrome-P450 induction along with significant decrease in catalase and superoxide dismutase was observed at 10.5 mg/kg and 12.6 mg/kg. The activity of glutathione peroxidase was increased significantly at all doses. In brain, no significant change was observed at 6.3 mg/kg. However, a significant increase in lipid peroxidation and glutathione peroxidase activity along with significant decrease in the activity of glutathione, catalase and superoxide dismutase was observed at 10.5 mg/kg and 12.6 mg/kg. The activity of glutathione-S-transferase was decreased significantly in both liver and brain at 10.5 and 12.6 mg/kg. No significant alteration in the activity of glucose-6-phosphate dehydrogenase and glutathione reductase was observed in either liver or brain at any dose. Dose-dependent histopathological changes, observed in both liver and brain are also described. A significant increase in caspase-3 activity was observed at all doses in liver and at 10.5 and 12.6 mg/kg in brain. Sodium arsenite caused DNA cleavage into fragments and manifested as "DNA laddering", a hallmark of apoptosis.
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PMID:Arsenic-induced cell death in liver and brain of experimental rats. 1643 89

Arsenic is an environmental toxicant that recently has been shown to have anticancer activity against a number of types of cancer cells by inducing apoptosis. Glycogen synthase kinase-3 (GSK3), a serine/threonine kinase, is an important pro-apoptotic signaling enzyme. Although GSK3 has been shown to promote apoptosis caused by a wide variety of insults, a role for GSK3 in arsenic-induced apoptosis has not yet been identified. Investigation of the involvement of GSK3 in arsenite-induced apoptosis demonstrated that arsenite induced apoptosis in SH-SY5Y human neuroblastoma cells, activating the executioner caspase-3 which caused cleavage of poly-ADP ribose-polymerase (PARP). Two selective GSK3 inhibitors, lithium and SB216763, attenuated caspase-3 activation and PARP cleavage induced by arsenite treatment indicating that GSK3 contributed to arsenite-induced apoptosis. Apoptotic signaling following exposure to arsenite involved cytochrome C release from mitochondria, and this was reduced by inhibition of GSK3 indicating that GSK3 promotes arsenite-induced apoptotic signaling upstream of mitochondrial disruption. Moreover, arsenite induced the translocation of Bax and p53 to the mitochondria and the activation-associated oligomerization of Bax, and these crucial events were reduced by inhibition of GSK3, indicating that GSK3 promotes arsenite-induced apoptosis by facilitating signals leading to mitochondrial apoptotic events. Taken together, the findings from this study reveal that GSK3 promotes arsenite-induced apoptosis by facilitating signaling leading to disruption of mitochondria.
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PMID:GSK3 promotes arsenite-induced apoptosis via facilitation of mitochondria disruption. 1784 3

Arsenic compounds have been traditionally used to treat a variety of ailments, including skin diseases. Our previous study identified the extract of realgar to possess potent antiproliferative action on HaCaT cells. The present study aimed at evaluating whether several inorganic arsenics found in realgar also possess similar antiproliferative properties. The results showed that arsenic trioxide, arsenic pentoxide, and arsenic iodide had significant antiproliferative action on HaCaT cells, with IC(50) values at 2.4, 16, and 6.8 microM, respectively. However, these compounds only modestly inhibited the growth of Hs-68 cells, a normal human skin fibroblast cell line, with IC(50) values at 43.4, 223, and 89 microM, respectively, conferring a favorable toxicity profile. In mechanistic studies, all three compounds caused DNA fragmentation as demonstrated by gel electrophoresis and the terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling method. Morphologically, nuclear condensation and DNA fragmentation were observed when the cells were exposed to arsenic compounds. Cell cycle analysis with propidium iodide (PI) staining demonstrated the appearance of sub-G(1) peak and cell arrest at the G(1) phase in the presence of these compounds. Quantitative analysis by annexin V-PI staining revealed that the arsenic-induced apoptotic event was dose-dependent. Moreover, the arsenic compounds were able to activate caspase-3 expression when examined by Western blot analysis. Our experimental data unambiguously demonstrated that induction of cellular apoptosis was mainly responsible for the observed antiproliferation brought about by the arsenic compounds on HaCaT keratinocytes, suggesting that these arsenic compounds are putative agents from which psoriasis-treating topical formulae could be developed.
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PMID:Arsenic trioxide, arsenic pentoxide, and arsenic iodide inhibit human keratinocyte proliferation through the induction of apoptosis. 1845 18

Arsenic (As) is a well-known environmental toxicant and carcinogen as well as an effective chemotherapeutic agent. The underlying mechanism of this dual capability, however, is not fully understood. Tumor suppressor gene p53, a pivotal cell cycle checkpoint signaling protein, has been hypothesized to play a possible role in mediating As-induced toxicity and therapeutic efficiency. In this study, we found that arsenite (As(3+)) induced apoptosis and cell cycle arrest in a dose-dependent manner in both p53(+/+) and p53(-/-) mouse embryonic fibroblasts (MEFs). There was, however, a distinction between genotypes in the apoptotic response, with a more prominent induction of caspase-3 in the p53(-/-) cells than in the p53(+/+) cells. To examine this difference further, a systems-based genomic analysis was conducted comparing the critical molecular mechanisms between the p53 genotypes in response to As(3+). A significant alteration in the Nrf2-mediated oxidative stress response pathway was found in both genotypes. In p53(+/+) MEFs, As(3+) induced p53-dependent gene expression alterations in DNA damage and cell cycle regulation genes. However, in the p53(-/-) MEFs, As(3+) induced a significant up-regulation of pro-apoptotic genes (Noxa) and down-regulation of genes in immune modulation. Our findings demonstrate that As-induced cell death occurs through a p53-independent pathway in p53 deficient cells while apoptosis induction occurs through p53-dependent pathway in normal tissue. This difference in the mechanism of apoptotic responses between the genotypes provides important information regarding the apparent dichotomy of arsenic's dual mechanisms, and potentially leads to further advancement of its utility as a chemotherapeutic agent.
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PMID:Gene expression profiling analysis reveals arsenic-induced cell cycle arrest and apoptosis in p53-proficient and p53-deficient cells through differential gene pathways. 1892 88


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