Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Luteolin was isolated from Scutellaria barbata D. Don (S. barbata). In the present study, we examined the underlying molecular mechanism of luteolin and its effect on in vivo tumor growth of Lewis lung carcinoma (LLC) cells. Luteolin exhibited antiproliferative activity against LLC cells with IC50 of 12 microM. Luteolin effectively increased Annexin-V-positive cells as well as sub G1 DNA portion as seen on flow cytometric analysis. Western blotting has revealed that luteolin effectively activates caspase 9 and 3, cleaves poly (ADP-ribose) polymerase (PARP), and increases the ratio of Bax/Bcl-2. Furthermore, mitochondrial membrane potential was reduced by luteolin as seen on fluorescence microscopy. Luteolin downregulated the expression of extracellular signal-regulated kinase (ERK) and Akt in a concentration-dependent manner. In addition, luteolin significantly inhibited the growth of LLC cells implanted on the flank of mice to 40% and 60% of untreated control group values at 2 mg/kg and 10 mg/kg, respectively. Similarly, luteolin significantly reduced the expression of proliferating cell nuclear antigen (PCNA) as well as increased the expression of terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) in tumor section of LLC-bearing mice as determined by immunohistochemistry. Taken together, these results suggest that luteolin exerts antitumor activity by caspase activation and ERK/Akt inhibition.
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PMID:Caspase activation and extracellular signal-regulated kinase/Akt inhibition were involved in luteolin-induced apoptosis in Lewis lung carcinoma cells. 1741 Jun 45

Luteolin was isolated from Scutellaria barbata D. Don (S. barbata). In the present study, we examined the underlying molecular mechanism of luteolin and its effect on in vivo tumor growth of Lewis lung carcinoma (LLC) cells. Luteolin exhibited antiproliferative activity against LLC cells with IC50 of 12 microM. Luteolin effectively increased Annexin-V-positive cells as well as sub G1 DNA portion as seen on flow cytometric analysis. Western blotting has revealed that luteolin effectively activates caspase 9 and 3, cleaves poly (ADP-ribose) polymerase (PARP), and increases the ratio of Bax/Bcl-2. Furthermore, mitochondrial membrane potential was reduced by luteolin as seen on fluorescence microscopy. Luteolin downregulated the expression of extracellular signal-regulated kinase (ERK) and Akt in a concentration-dependent manner. In addition, luteolin significantly inhibited the growth of LLC cells implanted on the flank of mice to 40% and 60% of untreated control group values at 2 mg/kg and 10 mg/kg, respectively. Similarly, luteolin significantly reduced the expression of proliferating cell nuclear antigen (PCNA) as well as increased the expression of terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) in tumor section of LLC-bearing mice as determined by immunohistochemistry. Taken together, these results suggest that luteolin exerts antitumor activity by caspase activation and ERK/Akt inhibition.
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PMID:Caspase activation and extracellular signal-regulated kinase/Akt inhibition were involved in luteolin-induced apoptosis in Lewis lung carcinoma cells. 1738 57

Transforming growth factor beta-1 (TGFbeta-1) is a regulator of cell proliferation, differentiation and apoptosis. Doxorubicin (adriamycin), an anthracycline drug causing double-strand DNA breaks, is widely used in anticancer chemotherapy. Here we demonstrated that TGFbeta-1 enhanced cytotoxic (proapoptotic) action of doxorubicin towards cultured human lung carcinoma A549 cells. Western-blot analysis and immunocytochemistry were used to show that doxorubicin induced PARP degradation in A549 cells, and TGFbeta-1 enhanced that action of the drug. The obtained results suggest a possibility of biomodulating effect of TGFbeta-1 on tumor cell treatment with doxorubicin.
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PMID:Transforming growth factor beta-1 enhances cytotoxic effect of doxorubicin in human lung adenocarcinoma cells of A549 line. 1741 94

Guggulsterone is a plant polyphenol traditionally used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, possibly through an anti-inflammatory mechanism. Whether this steroid has any role in cancer is not known. In this study, we found that guggulsterone inhibits the proliferation of wide variety of human tumor cell types including leukemia, head and neck carcinoma, multiple myeloma, lung carcinoma, melanoma, breast carcinoma, and ovarian carcinoma. Guggulsterone also inhibited the proliferation of drug-resistant cancer cells (e.g., gleevac-resistant leukemia, dexamethasone-resistant multiple myeloma, and doxorubicin-resistant breast cancer cells). Guggulsterone suppressed the proliferation of cells through inhibition of DNA synthesis, producing cell cycle arrest in S-phase, and this arrest correlated with a decrease in the levels of cyclin D1 and cdc2 and a concomitant increase in the levels of cyclin-dependent kinase inhibitor p21 and p27. Guggulsterone-induced apoptosis as indicated by increase in the number of Annexin V- and TUNEL-positive cells, through the downregulation of anti-apoptototic products. The apoptosis induced by guggulsterone was also indicated by the activation of caspase-8, bid cleavage, cytochrome c release, caspase-9 activation, caspase-3 activation, and PARP cleavage. The apoptotic effects of guggulsterone were preceded by activation of JNK and downregulation of Akt activity. JNK was needed for guggulsterone-induced apoptosis, inasmuch as inhibition of JNK by pharmacological inhibitors or by genetic deletion of MKK4 (activator of JNK) abolished the activity. Overall, our results indicate that guggulsterone can inhibit cell proliferation and induce apoptosis through the activation of JNK, suppression of Akt, and downregulation of antiapoptotic protein expression.
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PMID:Guggulsterone inhibits tumor cell proliferation, induces S-phase arrest, and promotes apoptosis through activation of c-Jun N-terminal kinase, suppression of Akt pathway, and downregulation of antiapoptotic gene products. 1747 22

Farnesol (FOH) and other isoprenoid alcohols induce apoptosis in various carcinoma cells and inhibit tumorigenesis in several in vivo models. However, the mechanisms by which they mediate their effects are not yet fully understood. In this study, we show that FOH is an effective inducer of apoptosis in several lung carcinoma cells, including H460. This induction is associated with activation of several caspases and cleavage of poly(ADP-ribose) polymerase (PARP). To obtain insight into the mechanism involved in FOH-induced apoptosis, we compared the gene expression profiles of FOH-treated and control H460 cells by microarray analysis. This analysis revealed that many genes implicated in endoplasmic reticulum (ER) stress signaling, including ATF3, DDIT3, HERPUD1, HSPA5, XBP1, PDIA4, and PHLDA1, were highly up-regulated within 4 h of FOH treatment, suggesting that FOH-induced apoptosis involves an ER stress response. This was supported by observations showing that treatment with FOH induces splicing of XBP1 mRNA and phosphorylation of eIF2alpha. FOH induces activation of several mitogen-activated protein kinase (MAPK) pathways, including p38, MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK, and c-jun NH2-terminal kinase (JNK). Inhibition of MEK1/2 by U0126 inhibited the induction of ER stress response genes. In addition, knockdown of the MEK1/2 and JNK1/2 expression by short interfering RNA (siRNA) effectively inhibited the cleavage of caspase-3 and PARP and apoptosis induced by FOH. However, only MEK1/2 siRNAs inhibited the induction of ER stress-related genes, XBP1 mRNA splicing, and eIF2alpha phosphorylation. Our results show that FOH-induced apoptosis is coupled to ER stress and that activation of MEK1/2 is an early upstream event in the FOH-induced ER stress signaling cascade.
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PMID:Farnesol-induced apoptosis in human lung carcinoma cells is coupled to the endoplasmic reticulum stress response. 1769

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.
Lung Cancer 2009 02
PMID:Ellipticine-induced apoptosis depends on Akt translocation and signaling in lung epithelial cancer cells. 2759 91

Pyrogallol, a catechin compound, is an active component of Emblica officinalis extracts and has an anti-proliferative effect on some human cancer cell lines. In our preliminary study, pyrogallol had highly cytotoxic effect on human lung cancer cell lines and less effect on human bronchial epithelium cell line. This study was performed to investigate the beneficial effect of pyrogallol on human lung cancer cell lines - H441 (lung adenocarcinoma) and H520 (lung squamous cell carcinoma). The MTT (cytotoxic) data showed the inhibition growth of lung cancer cells followed pyrogallol treatment. The cell cycle of lung cancer cells was arrested in G2/M phase using flow cytometry. Using Western blot analysis, the cell cycle related proteins - cyclin B1 and Cdc25c were decreased in a time-dependent manner and the phosphorylated Cdc2 (Thr14) was increased within 4h pyrogallol treatment. Moreover, the higher cleavage of poly (ADP)-ribose polymerase (PARP), the increased of Bax concurrent with the decreased of Bcl-2 indicated that pyrogallol treatment resulted in apoptosis of lung cancer cells. The cell apoptosis was also directly demonstrated using Annexin V-FITC and TUNEL stain. Additionally, the tumoricidal effect of pyrogallol was measured using a xenograft nude mice model. After 5 weeks of pyrogallol treatment could cause the regression of tumor. Taken in vitro and in vivo studies together, these results suggest that pyrogallol can be developed as a promising anti-lung cancer drug particular for the non-small cell lung cancer (NSCLC).
Lung Cancer 2009 Nov
PMID:Pyrogallol induces G2-M arrest in human lung cancer cells and inhibits tumor growth in an animal model. 1923 5

Although Ocimum sanctum has been used extensively for its medicinal values in India and China, its antitumor activity against human nonsmall cell lung carcinoma (NSCLC) A549 cells has not been investigated until now. Therefore, the antitumor mechanism of ethanol extracts of Ocimum sanctum (EEOS) was elucidated in A549 cells in vitro and the Lewis lung carcinoma (LLC) animal model. EEOS exerted cytotoxicity against A549 cells, increased the sub-G1 population and exhibited apoptotic bodies in A549 cells. Furthermore, EEOS cleaved poly(ADP-ribose)polymerase (PARP), released cytochrome C into cytosol and simultaneously activated caspase-9 and -3 proteins. Also, EEOS increased the ratio of proapoptotic protein Bax/antiapoptotic protein Bcl-2 and inhibited the phosphorylation of Akt and extracellular signal regulated kinase (ERK) in A549 cancer cells. In addition, it was found that EEOS can suppress the growth of LLC inoculated onto C57BL/6 mice in a dose-dependent manner. Overall, these results demonstrate that EEOS induces apoptosis in A549 cells via a mitochondria caspase dependent pathway and inhibits the in vivo growth of LLC, suggesting that EEOS can be applied to lung carcinoma as a chemopreventive candidate.
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PMID:Ocimum sanctum induces apoptosis in A549 lung cancer cells and suppresses the in vivo growth of Lewis lung carcinoma cells. 1927 50

Both the root and stem bark of Mahonia species were popular folk medicines. The plant has several proven biological activities including anti-bacterial, anti-fungal, and anti-inflammatory effects. However, Mahonia has not been studied for its anticancer effects. In the present study, we made extracts from Mahonia oiwakensis (MOE), a selected species in Taiwan, and investigated their effects on various human lung cells. We found that MOE-induced apoptotic death in human A549 non-small-cell lung carcinoma (NSCLC) cells in a dose- and time-dependent manner. Treatment with the extracts also caused an increase in the sub-G1 fraction of cells, chromosome condensation, and DNA fragmentation. The mitochondrial-mediated pathway was implicated in this MOE-induced apoptosis as evidenced by the activation of the caspase cascade, cleavage of poly (ADP-ribose) polymerase (PARP), disruption of mitochondrial membrane potential, and release of cytochrome C. A higher ratio of Bax/Bcl-2 proteins and cleavage of Bid were also observed in MOE-induced cell apoptosis. In A549 tumor-xenografted nude mice, MOE also retarded in vivo proliferation (P<0.05) and induced apoptosis in tumor cells, as shown by a decrease in Ki-67-positive staining (P<0.05) and increased transferase-mediated dUTP nick-end labeling (TUNEL)-positive staining (P<0.05). In conclusion, MOE inhibits the growth of human lung cancer cells in vitro and in vivo, suggesting that it may have therapeutic potential against human lung cancer.
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PMID:The in vitro and in vivo apoptotic effects of Mahonia oiwakensis on human lung cancer cells. 1949 14

The root of Panax notoginseng is highly valued and commonly used in Oriental medicine. Although recent experimental data have revealed the proapoptotic potency of P. notoginseng extracts, the underlying molecular mechanisms of this apoptotic activity have not yet been studied in detail. In the present study, the effects of the water extract of P. notoginseng (WEPN) on the growth of human lung carcinoma cells were investigated. It was found that the exposure of A549 and NIC-H460 cells to WEPN resulted in growth inhibition and the induction of apoptosis in a dose-dependent manner. The WEPN treatment induced the upregulation of pro-apoptotic Bax, downregulation of anti-apoptotic Bcl-2 expression and loss of mitochondrial membrane potential (MMP), which was associated with the proteolytic activation of caspases and the concomitant degradation of poly(ADP ribose) polymerase (PARP) protein. However, the caspase-3-specific inhibitor z-DEVD-fmk blocked PARP degradation and increased the survival rate of WEPN-treated cells. Moreover, the activity of Akt was downregulated in WEPN-treated cells and the phosphatidylinositol-3 kinase (PI3K)/Akt inhibitor LY294002 sensitized the cells to WEPN-induced apoptosis through enhancing the activation of caspase-3 and loss of MMP. The results indicated that the major regulators of WEPN-induced apoptosis in human lung carcinoma cells are the Bcl-2 family and caspase-3, which are associated with mitochondrial dysfunction and dephosphorylation of the Akt signaling pathway.
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PMID:Induction of apoptosis in human lung carcinoma cells by the water extract of Panax notoginseng is associated with the activation of caspase-3 through downregulation of Akt. 1951 59


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