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)

Dracorhodin perchlorate, an anthocyanin red pigment, induces human premyelocytic leukemia HL-60 cell death through apoptotic pathway. Caspase -1, -3, -8, -9, and -10 inhibitors partially reversed the cell death induced by dracorhodin perchlorate. Caspase-3 and -8 were activated followed to the degradation of caspase-3 substrates, inhibitor of caspase-activated DNase (ICAD) and poly-(ADP-ribose) polymerase (PARP). Dracorhodin perchlorate up-regulated the expression ratio of mitochondrial proteins, Bax/Bcl-XL. The cell death was accompanied with phosphorylation of ERK, JNK and p38 MAPK and partially reduced by MEK inhibitor (PD98059), JNK MAPK inhibitor (SP600125) and p38 MAPK inhibitor (SB 203580). Taken together, dracorhodin perchlorate-induced apoptosis in HL-60 cells via up-regulation of Bax, activation of caspases and ERK/p38/JNK MAPKs.
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PMID:Dracorhodin perchlorate induces apoptosis in HL-60 cells. 1686 44

Cadmium poisoning has been known to result in a wide variety of cellular responses, including oxidative stress and kinase activation. It has been reported that ERK is activated following acute cadmium exposure, and this response is commonly seen as a classical ERK survival mechanism. Here, we analyzed different cell types for their responses to low concentrations of cadmium poisoning. We found that there is an association between cell susceptibility to cadmium toxicity and ERK activation. This activation is atypical, since it consists of a sustained ERK phosphorylation, that lasts up to 6 days post stimulation. This activation is associated with the appearance of cleaved caspases 8 and 3, processed PARP, and irreversible damage. Pharmacological inhibition of ERK phosphorylation results in the ability of cells to resist cadmium poisoning. Our data indicate that low cadmium concentrations result in an unconventional ERK sustained phosphorylation, which in turn leads to death signaling.
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PMID:Low dose cadmium poisoning results in sustained ERK phosphorylation and caspase activation. 1702 45

Bee venom (BV) has been known to inhibit proliferation and induce apoptosis in cancer cells. However, the molecular mechanisms involved in BV-induced apoptosis are still uncharacterized in human leukemic cells. In the present study, we report that BV induces apoptosis in leukemic U937 cells through downregulation of ERK and Akt signal pathway. Furthermore, BV-induced apoptosis was accompanied by downregulation of Bcl-2, activation of caspase-3 and a subsequent poly(ADP-ribose)polymerase (PARP) cleavages. The induction of apoptosis also was accompanied by the downregulation of the inhibitor of apoptosis protein (IAP) family proteins. Caspase-3 inhibitor, z-DEVD-fmk, was significantly capable of restoring cell viability and BV-induced apoptosis through caspase-3 activation was significantly attenuated in Bcl-2-overexpressing cells. These results indicate that downregulation of Bcl-2 plays a major role in the initiation as an activator of a caspase-3 involved with BV-induced apoptosis. BV also triggered the activation of p38 MAPK and JNK, and downregulation of ERK and Akt. PD98059 (an inhibitor of ERK) or LY294002 (an inhibitor of Akt), but not an inhibitor of p38 MAPK and JNK, significantly decreased cell viability and increased lactate dehydrogenase (LDH) release. The results indicated that key regulators in BV-induced apoptosis are Bcl-2 and caspase-3 in human leukemic U937 cells through downregulation of the ERK and Akt signal pathway.
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PMID:Key regulators in bee venom-induced apoptosis are Bcl-2 and caspase-3 in human leukemic U937 cells through downregulation of ERK and Akt. 1705 70

MEK/ERK pathways are frequently activated in acute myelogenous leukemia, and this signal pathway's inhibitor has made it an interesting candidate for cancer chemotherapy. Little is known, however, about the effects of cellular and molecular mechanisms on human leukemic U937 cells. In the present study, we found that treatment with PD98059 significantly arrests the G1 phase through up-regulation of cyclin-dependent kinase (Cdk) inhibitor, and produces morphological features of apoptosis in U937 cells, which were associated with poly(ADP-ribose)polymerase (PARP) cleavage and PLC-gamma1 degradation. PD98059 also decreased the Cdk-2, Cdk-4, cyclin D1, and cyclin E expression, and increased high levels of the mitotic inhibitors p16(INIa), p21(Waf1), and p27(Kip1). Also, Bcl-2's overexpression and a caspase-3 inhibitor z-DEVD-fmk significantly attenuated PD98059-induced apoptosis through the down-regulation of caspase-3 activity, but did not attenuate G1 phase arrest. Moreover, PD98059 down-regulated Akt phosphorylation and produced a synergy effect of apoptosis with LY294002 co-treatment. Thus, our results imply that PD98059-induced apoptosis is significantly involved in down-regulation of Bcl-2, caspase-3 activity, the Akt pathway, and some of the biological functions in U937 cells.
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PMID:PD98059 triggers G1 arrest and apoptosis in human leukemic U937 cells through downregulation of Akt signal pathway. 1716 15

In 15% to 30% of patients with acute myeloid leukemia (AML), aberrant proliferation is a consequence of a juxtamembrane mutation in the FLT3 gene (FMS-like tyrosine kinase 3-internal tandem duplication [FLT3-ITD]), causing constitutive kinase activity. ABT-869 (a multitargeted receptor tyrosine kinase inhibitor) inhibited the phosphorylation of FLT3, STAT5, and ERK, as well as Pim-1 expression in MV-4-11 and MOLM-13 cells (IC(50) approximately 1-10 nM) harboring the FLT3-ITD. ABT-869 inhibited the proliferation of these cells (IC(50) = 4 and 6 nM, respectively) through the induction of apoptosis (increased sub-G(0)/G(1) phase, caspase activation, and PARP cleavage), whereas cells harboring wild-type (wt)-FLT3 were less sensitive. In normal human blood spiked with AML cells, ABT-869 inhibited phosphorylation of FLT3 (IC(50) approximately 100 nM), STAT5, and ERK, and decreased Pim-1 expression. In methylcellulose-based colony-forming assays, ABT-869 had no significant effect up to 1000 nM on normal hematopoietic progenitor cells, whereas in AML patient samples harboring both FLT3-ITD and wt-FLT3, ABT-869 inhibited colony formation (IC(50) = 100 and 1000 nM, respectively). ABT-869 dose-dependently inhibited MV-4-11 and MOLM-13 flank tumor growth, prevented tumor formation, regressed established MV-4-11 xenografts, and increased survival by 20 weeks in an MV-4-11 engraftment model. In tumors, ABT-869 inhibited FLT3 phosphorylation, induced apoptosis (transferase-mediated dUTP nick-end labeling [TUNEL]) and decreased proliferation (Ki67). ABT-869 is under clinical development for AML.
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PMID:ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia. 1720 55

Previous studies have shown that oridonin, a diterpenoid isolated from Rabdosia rubescens, was able to inhibit proliferation and induce apoptosis in several cell types. But the mechanisms remain poorly understood. In this study, we investigated the apoptosis-inducing effect and mechanisms of action of oridonin in human osteosarcoma cells. Our results demonstrated that oridonin induced concentration- and time-dependent suppression of proliferation and activation of apoptosis in U2OS, MG63 and SaOS-2 osteosarcoma cell lines. Oridonin induced the release of cytochrome c accompanied by activation of caspase-9, caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP). These events were all inhibited by z-VAD-fmk, a universal inhibitor of caspases. Oridonin treatment dephosphorylated constitutively active AKT, FOXO transcription factor, and glycogen synthase kinase 3 (GSK3). In addition, oridonin decreased the phosphorylation of ERK and increased the phosphorylation of p38 MAPK and JNK. Furthermore, oridonin treatment down-regulated the expression of the inhibitor of apoptosis protein(IAP) in osteosarcoma cells. All together, our results suggested that oridonin is able to inactivate Akt and ERK and activate p38 MAPK and JNK signalling pathways in osteosarcoma cells causing the suppression of proliferation and induction of mitochondria- and caspase-dependent apoptosis.
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PMID:Oridonin induced apoptosis through Akt and MAPKs signaling pathways in human osteosarcoma cells. 1721 75

We examined the impact of EGFR-ERK signaling on poly (ADP-ribose) polymerase (PARP) activation following ionizing irradiation of human prostate cancer (PCa) cell lines displaying marked differences in ERK dependence. PARP activation was indicated by the appearance of polyADP-ribose, the incorporation of P32-labelled NADH, and by cellular NADH. EGFR-ERK signaling was manipulated through ligand activation or signal interruption using the tyrphostin AG1478, or MEK inhibitor PD 184352. EGF activation of ERK prior to irradiation was associated with a marked increase in PARP activation and decreased survival in both cell lines. Prior inactivation of PARP protected both cell lines from the initial decrease in NAD+ and improved the survival of LNCaP cells following combined EGF and IR treatment. MEK inhibitor PD 184352 also reduced PARP activation and improved LNCaP survival following EGF and IR treatment. These data imply that PARP activation following exposure to ionizing radiation is enhanced through EGFR-ERK signaling.
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PMID:Radiation-induced PARP activation is enhanced through EGFR-ERK signaling. 1729 9

A new NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), inhibited proliferation and induced apoptosis in human Burkitt lymphoma, HS-Sultan and Daudi cell lines. The activation of caspase-3 and the cleavage of caspase substrate PARP were observed after treatment with DHMEQ. The induction of apoptosis by DHMEQ was prevented by the pretreatment of Burkitt lymphoma cells with pan-caspase inhibitor, z-VAD-FMK. The expression of anti-apoptotic factors such as IAP-1 and XIAP was suppressed by DHMEQ. Phosphorylation of ERK and JNK was induced by DHMEQ. In conclusion, these results demonstrate that NF-kappaB might be an ideal target to develop for new anti-cancer drugs for Burkitt lymphoma.
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PMID:Targeting NF-kappaB and induction of apoptosis by novel NF-kappaB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) in Burkitt lymphoma cells. 1746 73

The study was aimed to investigate the molecular mechanisms of histone deacetylase inhibitor SAHA-induced apoptosis of acute myeloid leukemia cell line HL-60. The effect of SAHA on HL-60 cell proliferation was detected by MTT assay and the cell morphological changes were observed with Wright-Giemsa and Hoechst33342 staining. The cell cycle distribution was determined by flow cytometry and the expression of cell signaling proteins were detected by Western-blot analysis. The results showed that SAHA inhibited the proliferation of HL-60 cells in dose- and time-dependent manners, after 2 micromol/L SAHA exposure for 12 - 48 hours, the cell cycle was arrested at G(0)/G(1) phase and apoptotic cell death was confirmed by either defined apoptotic bodies stained by Hoechst33342, Western blot showed cleaved-PARP, which represents the activation of caspase 3. The Western blot analysis indicated the activation of two important survival signal pathways after SAHA treatment, the phosphorylation of Raf and its downstream ERK kinases were remarkable downregulated, whereas the phosphorylation of AKT and its downstream molecular mTOR were not changed. It is concluded that SAHA-induced apoptosis of HL-60 cells is mediated by inactivation of p44/42 MAPK signaling pathway.
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PMID:[Histone deacetylase inhibitor SAHA induces inactivation of MAPK signaling and apoptosis in HL-60 cells]. 1749 29

Ascites are commonly found in ovarian cancer patients with advanced disease and are rich in cellular components and growth-promoting factors. The purpose of this study was to assess the effect of malignant ascites on TRAIL-induced apoptosis. We demonstrate that malignant ascites obtained from women with advanced ovarian cancer protect tumor cells from TRAIL- and FasL-induced apoptosis but not against cisplatin-induced apoptosis. This antiapoptotic effect was consistently found among different malignant ascites while nonmalignant peritoneal fluids or conditioned medium from TRAIL-resistant cells failed to protect tumor cells against TRAIL killing. Malignant ascites strongly inhibits TRAIL-induced caspase-3 activation and PARP cleavage. Furthermore, ascites activate PI3K and its downstream target Akt and increases c-FLIP(S) protein levels without affecting ERK phosphorylation status. The antiapoptotic effect of malignant ascites is abrogated by the inhibition of PI3K with LY294002, by a specific inhibitor of Akt and by Akt siRNA. We further show that the pro-survival effect of ascites can be suppressed by down-regulation of c-FLIP(S). Our data indicate that malignant effusions protect against TRAIL-induced apoptosis by activating the PI3K/Akt pathway. These findings demonstrate that the tumor microenvironment may contribute to the resistance of ovarian cancer cells to death receptor-induced apoptosis.
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PMID:Malignant ascites protect against TRAIL-induced apoptosis by activating the PI3K/Akt pathway in human ovarian carcinoma cells. 1753 91


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