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)

It has been reported that tetrandrine induces cell cycle arrest and apoptosis in human cancer cells. In the present study, we investigated the role of PI3K/AKT/GSK3beta pathway in tetrandrine- induced G(1) arrest and apoptosis. In HT-29 cells, tetrandrine induced dephosphorylation of AKT, activation and nuclear translocation of GSK3beta as well as upregulation of p27(kip1). Activation of GSK3beta via AKT inhibitoion induced by tetrandrine resulted in enhanced phosphorylation and proteolysis of cyclin D(1), activation of caspase 3 and subsequent cleavage of PARP. Selective GSK3beta inhibitiors and GSK3beta siRNA attenuated tetrandrine-induced G(1) arrest and apoptosis. Similar to tetrandrine, transfection of wild-type GSK3beta led to G(1) arrest and apoptosis via downregulation of cyclin D(1) and cleavage of PARP. These findings suggest that tetrandrine induces G(1) arrest and apoptosis through PI3K/AKT/GSK3beta pathway and identify GSK3beta as an important mediator in the processes.
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PMID:Involvement of PI3K/AKT/GSK3beta pathway in tetrandrine-induced G1 arrest and apoptosis. 1869 64

Ellipticine and its analogues were reported as topoisomerase II inhibitors and promising antitumor agents. In this work, we showed that the growth of human non-small-cell-lung-cancer (NSCLC) epithelial cells A549 can be inhibited by ellipticine. The inhibitory effect was reverted by PI3K inhibitors. The sub-G(1) phase cells after ellipticine treatment appeared at the expense of those that accumulated first at S- and G(2)/M phases during the early stage of treatment. We showed that the progression leading to cell death was impaired by wortmannin, which reverted apoptosis by retaining cells at S- and G(2)/M transition states. The characteristic apoptosis marker p53 activation after treatment appeared first followed by poly(ADP-ribose)polymerase (PARP) fragmentation. They disappeared upon co-treatment with wortmannin and the apoptotic phenotype reversed. Furthermore, ellipticine regulated endogenous survival signaling by up-regulating phosphorylated Akt that returned to its basal level later. Furthermore, ellipticine induced nucleus translocalization of p53 and Akt and recruitment of autophagosomes. The autophagic-related cell death was interfered by wortmannin and the suppressed growth reverted. The Akt-related cell death also occurred in p53-deficient cells with stable expression of exogenous p53. The work showed that ellipticine-induced cytotoxicity in NSCLC cells was achieved through autophagy and apoptotic death as a result of Akt-modulation. Being a topoisomerase II inhibitor, ellipticine proved a regulator in autophagy-related cell death through corporation of p53 and Akt.
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PMID:Ellipticine-induced apoptosis depends on Akt translocation and signaling in lung epithelial cancer cells. 2759 91

Inhibitors of the epidermal growth factor receptor (EGFR) have generated considerable hope for cancer treatment, specifically for lung and breast cancers. Therefore, identification of a natural, nontoxic agent(s) as an inhibitor of EGFR is of considerable importance. Delphinidin, an anthocyanidin present in pigmented fruits and vegetables, possesses potent antioxidant and antiproliferative properties. In our study, employing EGFR positive breast cancer AU-565 cells and immortalized MCF-10A cells, we evaluated the effect of delphinidin on EGFR and its downstream signaling pathways. Delphinidin (5-40 microM; 3 hr) treatment of both AU-565 cells and MCF-10A cells inhibited the (i) phosphorylation of EGFR, (ii) activation of PI3K, (iii) phosphorylation of AKT and MAPK. Further, delphinidin treatment of AU-565 cells inhibited EGF-induced autophosphorylation of EGFR, AKT and MAPK, activation of PI3K and cell invasion. We then compared the growth inhibitory effects of delphinidin (5-40 microM; 48 hr), and found that it resulted in a decrease in cell growth of AU-565 and MCF-10A cells but had only minimal effects on normal mammary epithelial 184A1 cells. Treatment of AU-565 cells with delphinidin resulted in (i) induction of apoptosis, (ii) cleavage of PARP protein, (iii) activation of caspase-3 and (iv) downregulation of Bcl-2 with an increase in the expression of Bax. In summary, our study identifies a naturally occurring dietary agent delphinidin as an effective inhibitor of EGFR signaling in breast cancer cells. We suggest that delphinidin could be developed as an agent for the management of EGFR positive human cancers.
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PMID:Inhibition of epidermal growth factor receptor signaling pathway by delphinidin, an anthocyanidin in pigmented fruits and vegetables. 1862 29

Selenocystine (SeC) is a nutritionally available selenoamino acid with selective anticancer effects on a number of human cancer cell lines. The present study shows that SeC inhibited the proliferation of human breast adenocarcinoma MCF-7 cells in a time- and dose-dependent manner, through the induction of cell cycle arrest and apoptotic cell death. SeC-induced S-phase arrest was associated with a marked decrease in the protein expression of cyclins A, D1, and D3 and cyclin-dependent kinases (CDKs) 4 and 6, with concomitant induction of p21waf1/Cip1, p27Kip1, and p53. Exposure of MCF-7 cells to SeC resulted in apoptosis as evidenced by caspase activation, PARP cleavage, and DNA fragmentation. SeC treatment also triggered the activation of JNK, p38 MAPK, ERK, and Akt. Inhibitors of ERK (U0126) and Akt (LY294002), but not JNK (SP600125) and p38 MAPK (SB203580), suppressed SeC-induced S-phase arrest and apoptosis in MCF-7 cells. The findings establish a mechanistic link between the PI3K/Akt pathway, MAPK pathway, and SeC-induced cell cycle arrest and apoptosis in MCF-7 cells.
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PMID:Selenocystine induces S-phase arrest and apoptosis in human breast adenocarcinoma MCF-7 cells by modulating ERK and Akt phosphorylation. 1895 17

Casticin, a component from Vitex rotundifolia, widely used as an anti-inflammatory agent in Chinese traditional medicine, was reported to have anti-tumor activities. This study aims to examine the anti-leukemic activity of casticin on leukemia cells and its molecular mechanism. Cell viability was measured by MTT method; apoptosis and cell cycle arrest were determined by flow cytometry, AV-PI assay, and DNA fragmentation assay. Western blot were performed to measure the protein expression level. The cell morphology alteration was detected with immunofluorescent analysis and DAPI nuclear staining. Our results showed that the proliferation of leukemia cells, including K562, Kasumi-1, and HL-60, were inhibited by casticin in a time- and dose-dependent manner. The IC50, determined after 48 h incubation, was 5.95 microM, 4.82 microM, and 15.56 microM for K562, HL-60, and Kasumi-1, respectively. The cell cycle analysis demonstrated casticin treatment resulted in a significant G2/M accumulation, concomitant with upregulation of P21waf1 and P27kip1. The percentage of cells in G2/M increased with time of exposure and reached to its climax (75.3%) at 12 h after casticin treatment, and subsequently declined to 27% at 48 h. We found that casticin treatment induced remarkable apoptosis, evidenced by increased percentage of AV-positive PI-negative cells as well as the cleavage of PARP and caspase 3. In addition, DNA fragmentation assay showed the typical apoptotic DNA ladder in casticin-treated K562 cells. Mitotic catastrophe and decreased polymeric tubulin can also be observed in casticin-treated K562 cells. In addition, we found that PI3K/AKT pathway was activated; Ly294002, a PI3K/AKT specific inhibitor, can enhance the anti-leukemic effect of casticin. Taken together, these results demonstrated that casticin induced leukemic cell death via apoptosis and mitotic catastrophe, and could synergize with PI3K/AKT inhibitor, suggesting that casticin could be a promising therapeutic agent against leukemia.
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PMID:Casticin induces leukemic cell death through apoptosis and mitotic catastrophe. 1913 93

Kaempferol (3,4',5,7-tetrahydroxyflavone) is a flavonoid with anti- and pro-oxidant activity present in various natural sources. Kaempferol has been shown to posses anticancer properties through the induction of the apoptotic program. Here we report that treatment of the chronic myelogenous leukemia cell line K562 and promyelocitic human leukemia U937 with 50 microM kaempferol resulted in an increase of the antioxidant enzymes Mn and Cu/Zn superoxide dismutase (SOD). Kaempferol treatment induced apoptosis by decreasing the expression of Bcl-2 and increasing the expressions of Bax. There were also induction of mitochondrial release of cytochrome c into cytosol and significant activation of caspase-3, and -9 with PARP cleavage. Kaempferol treatment increased the expression and the mitochondria localization of the NAD-dependent deacetylase SIRT3. K562 cells stably overexpressing SIRT3 were more sensitive to kaempferol, whereas SIRT3 silencing did not increase the resistance of K562 cells to kaempferol. Inhibition of PI3K and de-phosphorylation of Akt at Ser473 and Thr308 was also observed after treating both K562 and U937 cells with kaempferol. In conclusion our study shows that the oxidative stress induced by kaempferol in K562 and U937 cell lines causes the inactivation of Akt and the activation of the mitochondrial phase of the apoptotic program with an increase of Bax and SIRT3, decrease of Bcl-2, release of cytochrome c, caspase-3 activation, and cell death.
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PMID:Kaempferol induces apoptosis in two different cell lines via Akt inactivation, Bax and SIRT3 activation, and mitochondrial dysfunction. 1916 Apr 23

The aim of this study was to investigate apoptotic effect of 2-methoxyestradiol (2-ME2) on K562 cells and its mechanism. K562 cells were treated with different concentrations of 2-ME2. MTT assay was used to examine the effect inducing growth inhibition. DNA fragmentation assay and Annexin V-FITC/PI staining were used to detect the effect of apoptosis. The change of mitochondrial transmembrane potential was analyzed by flow cytometry. The expressions of related gene mRNA and/or proteins were detected by RT-PCR and Western blot respectively. The results indicated that the 2-ME2 inhibited proliferation of K562 cells in a time- and dose-dependent manners and the concentration of 50% growth inhibition (IC(50)) was 2 micromol/L at 48 hours. 2-ME2 induced DNA ladder and significantly increased apoptosis in K562 cells when exposed to 2 micromol/L of 2-ME2 for 24, 48 and 72 hours, the result of Annexin-V/PI staining showed that rates of the apoptotic cells were 13.78%, 22.32% and 29.43% respectively, which was remarkably higher than that of control (1.78%) (p < 0.05). The FCM analysis showed that the mitochondrial transmembrane potential in K562 cells lowered after exposed to 1, 2 and 4 micromol/L of 2-ME2 for 24 hours. 2-ME2 down-regulated the expression of bcr/abl and bcl-2, up-regulated the expression of bax mRNA, and down-regulated protein expressions of bcl-2, procaspase-3, procaspase-9, PARP (116 kD) and p-Akt, and up-regulated expression of cytoplasmic Cyto-C and PARP 85 kD apoptosis-related cleavage fragment protein, but had no effect on total Akt protein in K562 cells after treated with 2 micromol/L of 2-ME2 for 24, 48 and 72 hours. It is concluded that the 2-ME2 can induce the apoptosis and inhibit the proliferation of K562 cells by increasing the ratio of bax/bcl-2, reducing the mitochondrial transmembrane potential, releasing cytochrome C to cytoplasm, initiating the mitochondrial apoptosis pathway and leading in turn to caspase-3 activation. These findings suggest that interfere PI3K/Akt signal pathway via down-regulating the expression of bcr/abl mRNA is implicated in the effect of 2-ME2 on K562 cells.
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PMID:[Mechanism underlying 2-methoxyestradiol inducing apoptosis of K562 cells]. 1937 63

Astragalus membranaceus has been used to ameliorate the side effects of antineoplastic drugs because of its immunomodulating nature. We had recently demonstrated that total Astragalus saponins (AST) possess anticarcinogenic and proapoptotic properties in human colon cancer cells and tumor xenograft. In this study, we identified NSAID-activated gene (NAG-1) as a potential molecular target of AST. The growth-inhibitory and proapoptotic effects of AST were assessed in a panel of human cancer cell lines. Hoechst 33342 nuclear staining, Annexin V-FITC/propidium iodide staining, Western immunoblotting, real-time PCR, luciferase reporter assay and electrophoretic mobility shift assay were conducted to determine the association of NAG-1 and related transcription factors with AST during its regulation of apoptotic activities. Moreover, the combined proapoptotic and NAG-1 promoting activities of AST and/or inhibitors of the PI3K-Akt pathway were also examined. AST caused overexpression of NAG-1, leading to PARP cleavage and apoptosis. The induction of NAG-1 promoter activity by the drug was associated with increased gene expression, in addition to prior increase in Egr-1 expression and DNA binding activity. AST-induced NAG-1 activation was intensified when PI3K inhibitor LY294002 or Akt inhibitor was co-treated and reversed by NAG-1 siRNA transfection. Nevertheless, the extent of NAG-1 induction could not be altered by the ERK inhibitor PD98059. Our results indicate that NAG-1 is a potential molecular target of AST in its antitumorigenic and proapoptotic actions, which would have additive effects when used along with PI3K-Akt inhibitors. The information obtained could facilitate future development of a novel target-specific chemotherapeutic agent with known molecular pathway.
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PMID:A novel anticancer effect of Astragalus saponins: Transcriptional activation of NSAID-activated gene. 1938 47

Radiation therapy, a mainstay for anti-tumor therapeutic regimens for a variety of tumor types, triggers tumor cell apoptotic pathways by either directly eliciting DNA damage or indirectly inducing the formation of oxygen radicals. In an effort to augment radiation therapy, we generated a double E1B 19 kDa- and E1B 55 kDa-deleted oncolytic adenovirus (Ad-DeltaE1B19/55). In combination with radiotherapy, greater cytotoxicity was observed for Ad-DeltaE1B19/55 than for the single E1B 55 kDa-deleted oncolytic Ad (Ad-DeltaE1B55). Consistent with this observation, higher levels of p53, phospho-p53, phospho-Chk1, phospho-Chk2, PI3K (phosphatidylinositol-3-kinase), phospho-AKT, cytochrome c, and cleavage of PARP (poly (ADP-ribose) polymerase) and caspase-3 were observed in cells treated with Ad-DeltaE1B19/55 compared with those treated with Ad-DeltaE1B55, indicating that the E1B 19 kDa present in Ad-DeltaE1B55 may partially block radiation-induced apoptosis. A significant therapeutic benefit was also observed in vivo when oncolytic Ads and radiation were combined. Tumors treated with Ad-DeltaE1B19/55 and radiation showed large areas of necrosis and apoptosis with the corresponding induction of p53. Finally, consistent with in vitro observations, the combination of Ad-DeltaE1B19/55 and radiation was more efficacious than the combination of Ad-DeltaE1B55 and radiation. Taken together, these results present a strong therapeutic rationale for combining radiation therapy with E1B 19 kDa-deleted oncolytic Ad.
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PMID:Double E1B 19 kDa- and E1B 55 kDa-deleted oncolytic adenovirus in combination with radiotherapy elicits an enhanced anti-tumor effect. 1949 43

Eicosanoids, the oxygenated metabolites of arachidonic acid (AA), mediate a variety of human diseases, such as cancer, inflammation and arthritis. To evaluate the role of eicosanoids in epidermoid carcinoma, the expression of AA metabolizing enzymes, such as lipoxygenases (LOXs) and cyclooxygenases (COXs), was analysed in a human epidermoid carcinoma cell line (A431). These studies revealed overexpression of 12-R-LOX and COX-2 in A431 cells. Baicalein (a 12-LOX inhibitor) and celecoxib (a COX-2 inhibitor) significantly reduced thymidine incorporation, whereas 12-(R)-HETE and 12-(S)-HETE (12-LOX metabolites) and PGE(2) (COX-2 metabolite) significantly enhanced thymidine incorporation, suggesting a role for these enzymes in the regulation of A431 cell proliferation. Further studies on the mechanism of cell death by baicalein and celecoxib revealed that the induction of apoptosis in A431 cells was associated with reduction in the Bcl-2/Bax ratio, release of cytochrome c, activation of caspase-3 and PARP cleavage. The apoptosis induced by baicalein and celecoxib was mediated by down regulation of ERK and PI3K-Akt pathways. Further, 12-(R)-HETE, 12-(S)-HETE and PGE(2) upregulated the p-ERK and p-Akt levels, suggesting the involvement of ERK and Akt pathways in the 12-LOX- and COX-2-mediated regulation of growth in A431 cells. Our findings suggest that 12-R-LOX and COX-2 play a critical role in the regulation of growth in epidermoid carcinoma and that their inhibitors may be of potential therapeutic importance.
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PMID:Inhibition of 12-LOX and COX-2 reduces the proliferation of human epidermoid carcinoma cells (A431) by modulating the ERK and PI3K-Akt signalling pathways. 1955 94


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