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: EC:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inorganic arsenic is considered a human carcinogen based principally on epidemiological evidence. Unlike most initiating chemicals, arsenic is inactive or extremely weak in its ability to directly induce gene mutations. Arsenite has been shown, however, to enhance mutagenicity when present with other agents such as UV radiation. Synergistic potentiation of chromosomal damage has been shown with co-treatment with DNA-crosslinking agents. Arsenite at low concentrations is known to be highly selective in reacting with closely spaced (vicinal) dithiol groups in proteins. Poly(ADP-ribose) polymerase (PARP) is known to contain such vicinal dithiol groups. Stimulation of PARP is an immediate response of eukaryotic cells to DNA strand breaks and has been implicated in DNA repair. The effect of treatment with sodium arsenite on PARP activity was assessed as follows: Molt-3 cells (a human T-cell lymphoma-derived cell line) in culture were treated for 24 h with concentrations of sodium arsenite ranging from 2.5 up to 25 microM. Speciation of inorganic arsenic and cell viability were determined. Cell cycle kinetics were measured by flow cytometry. Poly(ADP-ribose) synthesis was assayed using a palindromic decameric deoxynucleotide to stimulate enzyme activity. Results show that arsenite decreases PARP activity in a dose-dependent manner with an approximately 50% decrease in enzyme activity at 10 microM arsenite and 80% viability. The percent of cells in S-phase increases with increasing concentration of arsenite. These results provide further indication that arsenite may potentiate genetic damage through reaction with dithiols in DNA repair proteins such as PARP, perhaps resulting in interference with normal repair function.
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PMID:Inhibition of poly(ADP-ribose) polymerase by arsenite. 921 71

Arsenic trioxide (As(2)O(3)) can induce clinical remission in patients suffering from acute promyelocytic leukemia, through induction of apoptosis and activation of caspases. We investigated the potential use of As(2)O(3) in human gastric cancer and its possible mechanisms. Human gastric cancer cell lines AGS and MKN-28 were treated with various concentrations (0.1 to 100 microM) of As(2)O(3) for 24 to 72 hr. Apoptosis was determined by acridine orange staining, flow cytometry and DNA fragmentation. Protein levels of p53, p21(waf1/cip1), c-myc, bcl-2 and bax were detected by Western blotting. Effects of As(2)O(3) on caspase-3 protease activity, its protein concentration and cleavage of poly(ADP)-ribose polymerase (PARP) were also studied. As(2)O(3) inhibited cell growth and induced apoptosis in both cell lines, though AGS cells were more sensitive. As(2)O(3) induced apoptosis in AGS cells in a concentration- and time-dependent manner. Treatment resulted in a marked increase in p53 protein levels as early as 4 hr. Co-incubation with p53 anti-sense oligo-nucleotide suppressed As(2)O(3)-induced intracellular p53 over-expression and apoptosis. As(2)O(3) increased the activity of caspase-3, with appearance of its 17 kDa peptide fragment, and cleavage of PARP, with appearance of the 85 kDa cleavage product, both in parallel with the induction of apoptosis. Both the tripeptide caspase inhibitor zVAD-fmk and the specific caspase-3 inhibitor DEVD-fmk partially suppressed As(2)O(3)-induced caspase-3 activation and apoptosis. As(2)O(3) inhibits cell growth and induces apoptosis in gastric cancer cells, involving p53 over-expression and activation of caspase-3. The potential use of this compound in the treatment of gastric cancer is worth further investigation.
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PMID:Arsenic trioxide induces apoptosis in human gastric cancer cells through up-regulation of p53 and activation of caspase-3. 1114 41

Arsenic trioxide has recently been shown to inhibit growth and induce apoptosis in acute promyelocytic leukemia (APL), but little is known about the molecular mechanisms mediating these effects. Here we demonstrate that treatment of promonocytic U937 cells with arsenic trioxide leads to G2/M arrest which was associated with a dramatic increase in the levels of cyclin B and cyclin B-dependent kinase and apoptosis. We further show that apoptosis occurs after bcl-2 phosphorylation and caspase-3 activation followed by cleavage of PARP and PLC-gamma1 degradation and DNA fragmentation. The arsenic trioxide-induced apoptosis could be blocked by the protein synthesis inhibitor cycloheximide. In addition, pretreatment of U937 cells with the DNA polymerase inhibitor aphidicolin also blocked apoptosis, but did not cause the arrest of cells in the G2/M phase. The findings suggest that arsenic trioxide exerts its growth-inhibitory effects by modulating expression and/or activity of several key G2/M regulatory proteins. Furthermore, arsenic trioxide-mediated G2/M arrest correlates with the onset of apoptosis.
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PMID:Arsenic trioxide induces G2/M growth arrest and apoptosis after caspase-3 activation and bcl-2 phosphorylation in promonocytic U937 cells. 1152 58

Arsenic trioxide (As2O3) has been reported to induce apoptosis in human T-cell leukemia virus type-I (HTLV-I) infected T-cell lines and fresh adult T-cell leukemia (ATL) cells and to induce G1 phase accumulation in HTLV-I infected T-cell lines. The present study aimed to clarify the pathway of As2O3-induced apoptosis in HTLV-I infected T-cell lines, MT-1 and MT-2, and fresh ATL cells separated from peripheral blood of patients with acute or chronic type ATL. Cells were treated up to 72 h at clinically tolerable concentrations of As2O3 (1-2 micromol/l) shown to be safe in patients with acute promyelocytic leukemia (APL). Activation of caspases 3, 8, and 9, loss of mitochondrial transmembrane potential and cleavage of poly (adenosine diphosphate-ribose) polymerase (PARP) were observed during As2O3 treatment. Furthermore, prior exposure to a broad-spectrum caspase inhibitor blocked As2O3-induced apoptosis but not G1 phase accumulation. While pre-treatment with a CD95 receptor-blocking antibody (Ab) or a TNF-alpha neutralizing Ab did not show such inhibitions in these cells. In conclusion, As2O3 induces apoptosis in HTLV-I infected T-cell lines and fresh ATL cells through CD95 or TNF-alpha receptor independent caspase activation.
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PMID:Arsenic trioxide induces apoptosis in HTLV-I infected T-cell lines and fresh adult T-cell leukemia cells through CD95 or tumor necrosis factor alpha receptor independent caspase activation. 1214 93

Because of the poor therapeutic responsiveness of pancreatic cancer patients, new chemotherapeutic agents for pancreatic cancer would be extremely beneficial. The effects of arsenic trioxide in pancreatic cancer have not been explored. To evaluate the anti-pancreatic cancer effects of arsenic trioxide, three human pancreatic cell lines, HPAF, MiaPaCa-2 and PANC-1, were tested. Arsenic trioxide caused dose- and time dependent inhibition of pancreatic cancer cell proliferation. In parallel with inhibition of cell proliferation, arsenic trioxide induced significant morphological changes, including shrunken cytoplasm, membrane blebbing, and nuclear condensation consistent with apoptosis. Propidium iodide DNA staining showed an increase of the sub-G0/G1 cell population. The DNA fragmentation induced by arsenic trioxide in these three cell lines was confirmed by the TUNEL assay. Furthermore, Western blotting analysis indicated that caspase-3 was activated following arsenic trioxide as measured by procaspase-3 cleavage and PARP cleavage. These findings show that arsenic trioxide has potent anti-proliferative effects on human pancreatic cancer cells with induction of apoptosis in vitro.
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PMID:Arsenic trioxide inhibits proliferation and induces apoptosis in pancreatic cancer cells. 1217 5

Arsenic trioxide (As(2)O(3)) is highly effective in the treatment of acute promyelocytic leukemias that express the promyelocytic leukemia-retinoic acid receptor-alpha (PML-RARalpha) fusion protein. However, evidence has accumulated that As(2)O(3) induces apoptosis regardless of PML-RARalpha status. Here we show that, at clinically relevant concentrations, As(2)O(3) causes S and G(2)M phase arrest of both PML-RARalpha-positive and -negative leukemia cell lines, thus inhibiting their growth. Apoptotic cells are generated predominately from the G(2)M fraction. Using several independent methods, we demonstrate that the cells accumulated in the G(2)M peak consist primarily of cells arrested in the early stages of mitosis, prophase, prometaphase and metaphase. In mitotic cells, there was significant activation of caspases, PARP cleavage, and morphological changes characteristic of apoptosis. Unlike microtubule-active drugs that arrest cells in metaphase, arsenic trioxide did not affect the architecture of microtubules. Our data suggest that the antileukemic activities of arsenic may be a result of mitotic arrest which culminates in apoptosis.
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PMID:Arsenic trioxide arrests cells early in mitosis leading to apoptosis. 1242 31

Arsenite is a naturally occurring environmental pollutant of major concern, since adverse health effects including cancer of skin and internal organs have been attributed to chronic arsenic exposure especially via drinking water. Arsenite is not a significant inducer of point mutations but exerts clastogenic activities and interferes with various DNA repair systems at concentrations in the low micromolar range. Nevertheless, no single DNA repair protein exquisitely sensitive to arsenic has been identified. Here we report that poly(ADP-ribosyl)ation, which is predominantly mediated by poly(ADP-ribose) polymerase-1 (PARP-1), is inhibited at concentrations as low as 10 nM in cultured HeLa cells, closely matching arsenic concentrations in blood and urine of the general population. Since poly(ADP-ribosyl)ation is an immediate cellular response to DNA damage, playing a major role in DNA base excision repair and the maintenance of genomic stability, its inhibition by arsenite may add to the risk of cancer formation under low-exposure conditions.
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PMID:Very low concentrations of arsenite suppress poly(ADP-ribosyl)ation in mammalian cells. 1253 12

Arsenite (NaAsO(2)) has been shown to produce vascular dysfunction in many studies. Arsenite-induced damage to vascular endothelial cells represents one of the possible mechanisms causing leakage of the vascular endothelial barrier. To explore arsenite-induced vascular endothelial damage, we used primary porcine aortic endothelial cells (PAECs) as an in vitro system to test the effects of arsenite on signal transduction pathways and apoptosis. Here we demonstrated that arsenite exposure induced apoptosis accompanied by the occurrence of apoptotic signals including degradation of poly(ADP-ribose) polymerase (PARP) and CPP32 (cleavage/activation) and DNA ladder formation. By using the luciferase reporter assay, we demonstrated that arsenite exposure differentially activated two redox-sensitive transcription factors, NF-kappaB and AP-1. Lower levels of arsenite exposure (25 microM NaAsO(2), 24 h) induced co-activation of NF-kappaB and AP-1, accompanied by 9% total apoptosis. In contrast, higher levels of arsenite exposure (40 microM NaAsO(2), 24 h) induced higher levels of AP-1 activation, accompanied by 45% total apoptosis. Blockade of NF-kappaB or JNK activity further enhanced arsenite-induced apoptosis. Upregulation of JNK activity showed no effect on arsenite-induced apoptosis. Based on these data, we propose that activation of redox-sensitive transcription factors, NF-kappaB and AP-1, plays a very important role in the protection of PAECs from arsenite-induced apoptosis.
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PMID:The protective role of NF-kappaB and AP-1 in arsenite-induced apoptosis in aortic endothelial cells. 1294 53

Arsenic trioxide has recently been shown to inhibit growth and induce apoptosis in a variety of hematologic malignancies, but very little is known about its effects on solid tumors and especially on neuroblastoma cells that have self-differentiating characteristics. To demonstrate the growth inhibition induced in neuroblastoma cells (the SH-SY5Y and SK-N-AS cell line) and acute promyelocytic leukemia cells (HL-60) by arsenic trioxide (As2O3), the viable cell numbers were counted after trypan blue staining. Apoptosis was assessed by the cell morphology, by flow cytometry with annexin-V staining, and by Western blot analysis for the apoptosis-related proteins (bcl-2 and PARP). To decide the dose for the clinical application of As2O3, normal peripheral blood lymphocytes were also examined. The growth and survival of the SH-SY5Y and SK-N-AS cells were markedly inhibited by As2O3 treatment at a 3 microM concentration before the changes of the normal lymphocytes were observed. The apoptotic cells showed a shrunken cell nucleus, and an increase in the number and balloon-like swelling of the mitochondria at 72 h after the As2O3 was added. Apoptosis of the annexin-V-positive cell proportion in the neuroblastoma cell lines was increased with increasing the exposure time and the concentration of As2O3, just like the HL-60 cells. Bcl-2 downregulation and PARP degradation were also noted all the cell lines, but these changes were not statistically significant among the 3 cell lines. Taken together, these results indicate that As2O3 is an excellent candidate as a therapeutic agent for the treatment of neuroblastoma.
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PMID:Morphological and biochemical changes induced by arsenic trioxide in neuroblastoma cell lines. 1616 54

Arsenite (As3+) has long been known to induce cancer and other degenerative diseases. Arsenite exerts its toxicity in part by generating reactive oxygen species. Identification of genetic factors that contribute to arsenic mutagenicity and carcinogenicity is critical for the treatment and prevention of arsenic exposure in human population. As poly(ADP-ribose) polymerase (PARP) is critical for genomic DNA stability, role of PARP-1 was evaluated in arsenic-induced cytotoxic and genotoxic effects. Our study revealed that telomere attrition, probably owing to arsenite-induced oxidative stress, was much more pronounced in PARP-1-/- mouse embryonic fibroblasts (MEF; 40%) compared with PARP-1+/+ MEFs (10-20%). Correlation observed between telomere reduction and apoptotic death in PARP-1 null cells strongly indicates that the telomere attrition might be a trigger for enhanced apoptotic death after arsenite treatment. Elevated DNA damage detected by alkaline comet assay points to an impaired repair ability of arsenite-induced DNA lesions in PARP-1-/- MEFs. Consistent with elevated DNA damage, increased micronuclei induction reflecting gross genomic instability was also observed in arsenite-treated PARP-1-/- MEFs. Microarray analysis has revealed that arsenite treatment altered the expression of about 311 genes majority of which have known functions in cellular responses to stress/external stimulus and cell growth and/or maintenance. Our results suggest an important role for PARP-1 gene product in the maintenance of chromosome-genome stability in response to arsenite-induced DNA damage.
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PMID:Lack of poly(ADP-ribose) polymerase-1 gene product enhances cellular sensitivity to arsenite. 1632 46


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