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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been shown that expression of the RIalpha subunit of cyclic AMP (cAMP)-dependent protein kinase is enhanced in human cancer cell lines, primary tumors, and cells after transformation. Using an antisense strategy, we have shown that RIalpha has a role in neoplastic cell growth in vitro and in vivo. In the present study, we have investigated the sequence- and target-specific effects of exogenous RIalpha antisense oligodeoxynucleotides (ODNs) and endogenous antisense gene on tumor growth, apoptosis, and cAMP signaling in androgen-insensitive prostate cancer cells, both in vitro and in nude mice. Here, we show that an RIalpha antisense, RNA/DNA mixed backbone ODN exerts a reduction in RIalpha expression at both the mRNA and protein levels, up-regulation of both the RIIbeta subunit of cAMP-dependent protein kinase or protein kinase A and c-AMP-phosphodiesterase IV expression, and inhibition of cell growth. Growth inhibition was accompanied by changes in cell morphology and the appearance of apoptotic nuclei. In addition, Bcl-2 hyperphosphorylation; increase in the proapoptotic proteins Bax, Bak, and Bad; and Bad hypophosphorylation occurred in the antisense-treated cells. These effects of exogenously supplied antisense ODN mirrored those induced by endogenous antisense gene overexpression. The RIalpha antisense ODNs, which differed in sequence or chemical modification, promoted a sequence- and target-specific reduction in RIalpha protein levels and inhibited tumor growth in nude mice. These results demonstrate that in a sequence-specific manner, RIalpha antisense, via efficient depletion of the growth stimulatory molecule RIalpha, induces growth inhibition, apoptosis, and phenotypic (cell morphology) changes, providing an innovative approach to combat hormone-insensitive prostate cancer cell growth.
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PMID:Protein kinase A RIalpha antisense inhibition of PC3M prostate cancer cell growth: Bcl-2 hyperphosphorylation, Bax up-regulation, and Bad-hypophosphorylation. 1183 45

Docetaxel, a semisynthetic taxane, improves the survival of stage IIIB and IV non-small cell lung cancer patients. However, the 5-year survival remains poor, and few patients experience a complete remission. In this report, we evaluated the effects of exisulind, a novel proapoptotic agent that is a sulfone metabolite of sulindac, in combination with docetaxel on the growth of the human non-small cell lung cancer cell line A549 in vitro and in vivo. Exisulind is a novel sulindac metabolite in that it does not inhibit cyclooxygenase enzymes and has been shown to induce apoptosis in a variety of human cancers by inhibiting cyclic GMP-dependent phosphodiesterase. Exisulind alone increased the fraction of cells in the G(1) phase of the cell cycle from 46% to 65%, whereas it decreased the fraction of cells in the S phase from 38% to 14%. Docetaxel increased the fraction of cells in the S phase from 17% to 19%, and 10 nM docetaxel increased the G2-M phase by 23%. Docetaxel alone induced apoptosis from 11% to 64% at 12-24 h after incubation. The combination of exisulind with concentrations of docetaxel (in concentrations that alone did not alter cell cycle distribution) reduced the G(1) accumulation induced by exisulind, increased the fraction of cells in G(2)-M (9-17%), and increased apoptosis (5-62%). The IC(50) for in vitro growth inhibition by exisulind alone was approximately 200 microM and 2.5 nM for docetaxel. The in vitro combination of exisulind and docetaxel produced an additive to synergistic growth inhibition. In athymic nude rats with A549 orthotopic lung cancers, both exisulind and docetaxel alone moderately prolonged survival, inhibited tumor growth and metastases, and increased apoptosis compared with control animals treated with a carrier. However, the combination of exisulind with docetaxel significantly prolonged survival (P = < 0.0004), inhibited tumor growth and metastases (P = < 0.0001), and increased apoptosis (P = < 0.001) when compared with control animals. These results provide rationale for conducting clinical trials using the combination of exisulind and docetaxel in patients with advanced lung cancer.
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PMID:Exisulind in combination with docetaxel inhibits growth and metastasis of human lung cancer and prolongs survival in athymic nude rats with orthotopic lung tumors. 1189 25

The mitogen-stimulated serine/threonine kinase p70S6k plays an important role in the progression of cells from G0/G1 to S phase of the cell cycle by translational up-regulation of a family of mRNA transcripts family of mRNA transcripts which contain polypyrimidine tract at their 5 transcriptional start site. Here, we report that p70S6k was constitutively phosphorylated and activated to various degrees in serum-deprived AGS, A2058, HT-1376, MG63, MCF7, MDA-MB-435S, MDA-MB-231 and MB-157. Rapamycin treatment induced a significant dephosphorylation and inactivation of p70S6k in all cancer cell lines, while wortmannin, a specific inhibitor of PI3-K, caused a mild dephosphorylation of p70S6k in AGS, MDA-MB-435S and MB-157. In addition, SQ20006, methylxanthine phosphodiesterase inhibitor, reduced the phosphorylation of p70S6k in all cancer cells tested. Consistent with inhibitory effect of rapamycin on p70S6k activity, rapamycin inhibited [3H]-thymidine incorporation and increased the number of cells at G0/G1 phase. Furthermore, these inhibitory effects were accompanied by the decrease in growth of cancer cells. Taken together, the results indicate that the antiproliferative activity of rapamycin might be attributed to cell cycle arrest at G0/G1 phase in human cancer cells through the inhibition of constitutively activated p70S6k of cancer cells and suggest p70S6k as a potential target for therapeutic strategies aimed at preventing or inhibiting tumor growth.
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PMID:Constitutive activation of p70S6k in cancer cells. 1243 6

Thalidomide is clinically useful in a number of cancers. Antitumor activity may be related to a number of known properties, including anti-tumor necrosis factor (TNF)-alpha and T-cell costimulatory and antiangiogenic activities. However, it may also involve direct antitumor effects. A series of second generation thalidomide analogues have been separated into two distinct groups of compounds, each with enhanced therapeutic potential, i.e., SelCIDs, which are phosphodiesterase (PDE) type IV inhibitors, and IMiDs, which have unknown mechanism(s) of action. We report here our efforts to determine direct antitumor effects of thalidomide and compounds from both groups. We found that one of the SelCID analogues (SelCID-3) was consistently effective at reducing tumor cell viability in a variety of solid tumor lines but had no effect on non-neoplastic cells. The antitumor activity was independent of known PDE4 inhibitory activity and did not involve cAMP elevation. Growth arrest was preceded by the early induction of G(2)-M cell cycle arrest, which led to caspase 3 mediated apoptosis. This was associated with increased expression of pro-apoptotic proteins and decreased expression of antiapoptotic bcl-2. Furthermore, extensive apoptosis in vivo was detected during SelCID-3-mediated inhibition of tumor growth in a murine xenotransplantation cancer model. Our results suggest that SelCID-3 represents a novel antitumor agent distinct from thalidomide and from previously characterized analogues with therapeutic potential against a range of solid tumors. This effect appears to be mediated via alterations in the expression of bcl-2 family proteins.
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PMID:A novel subclass of thalidomide analogue with anti-solid tumor activity in which caspase-dependent apoptosis is associated with altered expression of bcl-2 family proteins. 1256 1

Pentoxifylline (PTX) is a methylxanthine derivative that unspecifically inhibits phosphodiesterase activity and thus, it increases intracellular concentration of cyclic nucleotides. Currently, PTX is commonly and chronically used in peripheral blood vessel diseases. Besides its well-known influence on rheologic properties of blood, PTX has also been found to decrease secretion of some cytokines such as IL-12, TNF and IFN-gamma and thus it could exert immunomodulatory activity. Furthermore, PTX inhibits lymphocyte cytotoxicity affecting the perforin-dependent pathway, both in humans and animals. It has also been shown recently that in some murine models, PTX promotes tumor growth. Such a phenomenon, at least partially, could result from PTX-dependent inhibition of natural cytotoxicity. However, the detailed mechanism of PTX influence on cytotoxic activity in humans has not been established. We hypothesized that PTX-dependent inhibition of natural cytotoxicity could result from decrease in perforin expression. In this study, it was shown that pentoxifylline only moderately inhibits perforin expression at the mRNA level in human peripheral blood mononuclear cells (PBMC), and this effect seems to be independent of intracellular cAMP concentration. On the other hand, PTX did not significantly influence perforin expression at the protein level. These results suggest that in humans, contrary to murine models, inhibition of perforin-dependent natural cytotoxicity through pentoxifylline does not result from changes in perforin production. Presumably, influence of PTX on natural cytotoxicity could be caused by e.g. interference with lymphocyte degranulation. Moreover, also other possibilities, such as PTX influence on conformational changes of perforin molecules and/or its influence on susceptibility of target cells to pore-forming of polyperforins cannot be excluded.
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PMID:Influence of pentoxifylline on perforin expression in human PBMC. 1537 8

We have found that the synthetic compound CC-5079 potently inhibits cancer cell growth in vitro and in vivo by a novel combination of molecular mechanisms. CC-5079 inhibits proliferation of cancer cell lines from various organs and tissues at nanomolar concentrations. Its IC(50) value ranges from 4.1 to 50 nmol/L. The effect of CC-5079 on cell growth is associated with cell cycle arrest in G(2)-M phase, increased phosphorylation of G(2)-M checkpoint proteins, and apoptosis. CC-5079 prevents polymerization of purified tubulin in a concentration-dependent manner in vitro and depolymerizes microtubules in cultured cancer cells. In competitive binding assays, CC-5079 competes with [(3)H]colchicine for binding to tubulin; however, it does not compete with [(3)H]paclitaxel (Taxol) or [(3)H]vinblastine. Our data indicate that CC-5079 inhibits cancer cell growth with a mechanism of action similar to that of other tubulin inhibitors. However, CC-5079 remains active against multidrug-resistant cancer cells unlike other tubulin-interacting drugs, such as Taxol and colchicine. Interestingly, CC-5079 also inhibits tumor necrosis factor-alpha (TNF-alpha) secretion from lipopolysaccharide-stimulated human peripheral blood mononuclear cells (IC(50), 270 nmol/L). This inhibitory effect on TNF-alpha production is related to its inhibition of phosphodiesterase type 4 enzymatic activity. Moreover, in a mouse xenograft model using HCT-116 human colorectal tumor cells, CC-5079 significantly inhibits tumor growth in vivo. In conclusion, our data indicate that CC-5079 represents a new chemotype with novel mechanisms of action and that it has the potential to be developed for neoplastic and inflammatory disease therapy.
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PMID:The synthetic compound CC-5079 is a potent inhibitor of tubulin polymerization and tumor necrosis factor-alpha production with antitumor activity. 1642 30

The chemokine CXCL12 and its cognate receptor CXCR4 regulate malignant brain tumor growth and are potential chemotherapeutic targets. However, the molecular basis for CXCL12-induced tumor growth remains unclear, and the optimal approach to inhibiting CXCR4 function in cancer is unknown. To develop such a therapeutic approach, we investigated the signaling pathways critical for CXCL12 function in normal and malignant cells. We discovered that CXCL12-dependent tumor growth is dependent upon sustained inhibition of cyclic AMP (cAMP) production, and that the antitumor activity of the specific CXCR4 antagonist AMD 3465 is associated with blocking cAMP suppression. Consistent with these findings, we show that pharmacologic elevation of cAMP with the phosphodiesterase inhibitor Rolipram suppresses tumor cell growth in vitro and, upon oral administration, inhibits intracranial growth in xenograft models of malignant brain tumors with comparable efficacy to AMD 3465. These data indicate that the clinical evaluation of phosphodiesterase inhibitors in the treatment of patients with brain tumors is warranted.
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PMID:Blocking CXCR4-mediated cyclic AMP suppression inhibits brain tumor growth in vivo. 1723 75

An in vitro model of VEGF-A-induced angiogenesis was used to generate transcription profiles of human microvascular endothelial cells. Microarray analysis showed increased transcription of genes known to regulate angiogenesis, but also genes that previously have not been firmly associated with angiogenesis such as endocan, pinin, plakophilin, phosphodiesterase 4B and gelsolin. Increased endocan mRNA levels in response to VEGF-A in endothelial cells and in human renal cancer have previously been reported. We now show increased endocan protein levels in VEGF-A treated endothelial cells and in human renal clear cell carcinoma. Increased protein expression was observed both in tumor cells and in a subset of tumor vessels, while expression in normal kidney tissue was low. VEGF-A seemed to be a specific inducer of endocan transcription since FGF-2, PDGF-BB, HGF/SF and EGF did not alter expression levels. Inhibition of PI3K with LY294002 caused a 12-fold increase in endocan transcription suggesting a repressive function of PI3K. In contrast inhibition of Src or MEK, which are signaling pathways activated by VEGF-A, did not influence basal or VEGF-A-induced endocan levels. In conclusion our study shows that, among angiogenic growth factors, VEGF-A is a specific inducer of endocan transcription which is translated into increased protein levels in VEGF-A treated endothelial cells. Increased endocan protein expression in human renal cancer suggests a role in tumor growth.
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PMID:Endocan is a VEGF-A and PI3K regulated gene with increased expression in human renal cancer. 1736 27

Although it is often assumed that the antitumor effects of nonsteroidal anti-inflammatory drugs (NSAIDs) are due to inhibition of cyclooxgenase (COX) activity, specifically COX-2, there is accumulating evidence that COX-2 independent mechanisms can also play an important role. Studies with sulindac sulfone (Aptosyn) and related derivatives have revealed a novel pathway of tumor growth inhibition and apoptosis mediated by activation of the guanosine 3',5' monophosphate (cGMP)-dependent enzyme protein kinase G (PKG). The present study indicates that concentrations of the NSAIDs celecoxib, indomethacin, and meclofenamic acid that inhibit growth of SW480 human colon cancer cells inhibit subcellular cGMP-phosphodiesterase (PDE) enzymatic activity and in intact cells induce a two- to threefold increase in intracellular levels of cGMP. This is associated with phosphorylation of the protein VASP, a marker of PKG activation, activation of JNK1 and a decrease in cellular levels of cyclin D1; effects seen with other agents that cause activation of PKG in these cells. On the other hand even a high concentration of the COX-2 specific inhibitor rofecoxib (500 microM) did not inhibit growth of SW480 cells. Nor did rofecoxib inhibit cGMP-PDE activity or cause other changes related to PKG activation in these cells. Since activation of the PKG pathways by celecoxib, indomethacin, and meclofenamic acid in this cell culture system required high concentrations of these compounds, it remains to be determined whether activation of this pathway contributes to the in vivo antitumor effects of specific NSAIDs.
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PMID:Celecoxib-induced growth inhibition in SW480 colon cancer cells is associated with activation of protein kinase G. 1816 59

Tumor cell migration, invasion, and angiogenesis are important determinants of tumor aggressiveness, and these traits have been associated with the motility stimulating protein autotaxin (ATX). This protein is a member of the ectonucleotide pyrophosphatase and phosphodiesterase family of enzymes, but unlike other members of this group, ATX possesses lysophospholipase D activity. This enzymatic activity hydrolyzes lysophosphatidylcholine to generate the potent tumor growth factor and motogen lysophosphatidic acid (LPA). In the current study, we show a link between ATX expression, LPA, and vascular endothelial growth factor (VEGF) signaling in ovarian cancer cell lines. Exogenous addition of VEGF-A to cultured cells induces ATX expression and secretion, resulting in increased extracellular LPA production. This elevated LPA, acting through LPA(4), modulates VEGF responsiveness by inducing VEGF receptor (VEGFR)-2 expression. Down-regulation of ATX secretion in SKOV3 cells using antisense morpholino oligomers significantly attenuates cell motility responses to VEGF, ATX, LPA, and lysophosphatidylcholine. These effects are accompanied by decreased LPA(4) and VEGFR2 expression as well as by increased release of soluble VEGFR1. Because LPA was previously shown to increase VEGF expression in ovarian cancer, our data suggest a positive feedback loop involving VEGF, ATX, and its product LPA that could affect tumor progression in ovarian cancer cells.
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PMID:Positive feedback between vascular endothelial growth factor-A and autotaxin in ovarian cancer cells. 1833 45


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