Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Raf-1 protein serine/threonine kinase plays an important role in cell proliferation and cell survival. We have previously described a novel cationic liposome-entrapped formulation of raf antisense oligodeoxyribonucleotide (LErafAON) and its use as a radiosensitizer. The aim of this study was to examine the effect of combination of LErafAON and a chemotherapeutic agent on growth of human prostate (PC-3) and pancreatic tumor xenografts in athymic mice (Aspc-1 and Colo 357). In PC-3 tumor-bearing mice, administration of a combination of LErafAON (i.v., 25 mg/kg/dose, x10/16) and cisplatin (i.v., 11.0 mg/kg/dose, x3), epirubicin (EPI) (i.v., 9.0 mg/kg/dose, x3) or mitoxantrone (MTO) (i.v., 2.5 mg/kg/dose, x3) led to enhanced tumor growth inhibition as compared with single agents (LErafAON+cisplatin versus cisplatin, p<0.0002, n=8; LErafAON+EPI versus EPI, p<0.0001, n=6; LErafAON+MTO versus MTO, p<0.05, n=5). In prostate or pancreatic tumor-bearing mice, combination of LErafAON (i.v., 25 mg/kg/dose, x10/13) with docetaxel (Taxotere) (i.v., 5, 7.5 or 10 mg/kg/dose, x2/4) led to tumor regression or enhanced growth inhibition as compared with single agents (PC-3: LErafAON+Taxotere versus Taxotere, p<0.02, n=7; Aspc-1: LErafAON+Taxotere versus Taxotere, p<0.03, n=5; Colo 357: LErafAON+Taxotere versus Taxotere, p<0.04, n=7). Combination of LErafAON (i.v., 25 mg/kg/dose, x10/13) with gemcitabine (i.v., 75 mg/kg/dose, x4/6) also caused a significant tumor growth inhibition in the two pancreatic carcinoma models studied (Aspc-1: LErafAON+gemcitabine versus gemcitabine, p<0.0001, n=7; Colo 357: LErafAON+gemcitabine versus gemcitabine, p<0.002, n =5). LErafAON treatment (i.v., 25 mg/kg/dose, x10) caused inhibition of Raf-1 protein expression in these tumor tissues (around 25-60%, n=4-7). Interestingly, Taxotere treatment per se also led to decreased steady state level of Raf-1 protein in PC-3 and Aspc-1 tumor tissues (i.v., 10 mg/kg/dose, x1 or 7.5 mg/kg/dose, x2; around 25-80%, n=2/6). Present studies demonstrate enhanced tumor growth inhibition or regression in response to a combination of a chemotherapeutic drug and LErafAON. These data provide a proof-of-principle for the clinical use of LErafAON in combination with chemotherapy for cancer treatment.
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PMID:Combination with liposome-entrapped, ends-modified raf antisense oligonucleotide (LErafAON) improves the anti-tumor efficacies of cisplatin, epirubicin, mitoxantrone, docetaxel and gemcitabine. 1501 58

Raf-1 protein kinase plays an important role in cell growth, proliferation and cell survival. We have previously described the use of liposome-entrapped antisense raf oligonucleotide (LErafAON) to inhibit Raf-1 expression resulting in tumor growth inhibition and radiosensitization. The present study was undertaken to evaluate the chemosensitization effects of LErafAON in combination with doxorubicin or paclitaxel on a panel of human tumor xenografts. LErafAON (25.0 mg/kg i.v. x 10) displayed significant antitumor activity (P<0.05) when administered as a single agent in prostate (PC-3), lung (A549) and breast (MDA-MB 231) carcinoma models. Doxorubicin (1.0-4.0 mg/kg i.v. per week x 3) and paclitaxel (1.0-4.0 mg/kg i.v. on alternate days x 3) were administered as single agents at non-toxic doses that led to only minimal to moderate antitumor activity. However, a combination of LErafAON with doxorubicin or paclitaxel led to significantly enhanced antitumor activity in all the tumor types tested (PC-3, P<0.03; A549, P<0.035; MDA-MB 231, P<0.045) as compared with LErafAON alone or chemotherapeutic agents alone treated groups. This effect of chemosensitization appeared to be sequence-specific because a mismatch control oligonucleotide continued to show significant tumor growth. Additionally, no inhibition in Raf-1 expression in MDA-MB 231 tumor tissue was observed with mismatch oligonucleotide treatment. On the other hand, LErafAON treatment led to >75% inhibition of Raf-1 expression in tumor tissue. These preclinical observations support the use of LErafAON in combination with chemotherapeutic agents to improve the treatment of human cancers.
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PMID:Enhanced therapeutic effects of doxorubicin and paclitaxel in combination with liposome-entrapped ends-modified raf antisense oligonucleotide against human prostate, lung and breast tumor models. 1506 40

Abnormally suppressed levels of cyclin-dependent kinase inhibitors (CKIs) are associated with aggressive androgen-independent prostate cancer and contribute to uncontrolled proliferation. The androgen-independent human prostate cancer cell lines, LNCaP-104R1, ALVA31 and PC-3, express low levels of the CKI, p21(CIP1), compared to the less-malignant, androgen-dependent LNCaP cells. We investigated the mechanism underlying this suppression by examining the role of Rho GTPases, signaling proteins that play important roles in cell cycle progression, at least in part through regulation of CKIs. Inhibition of Rac1 induced p21 expression in androgen-independent lines but had no effect on the higher p21 levels characteristic of LNCaP cells. This induction of p21 was functionally significant as evidenced by inhibition of cyclin-dependent kinase 2 activity and decreased cell proliferation. Conversely, overexpression of constitutively active Rac1 suppressed the higher p21 levels seen in LNCaP cells. Thus, Rac1 activity is both necessary and sufficient for suppression of p21 in prostate cancer cells. Furthermore, Rac1 activity was significantly higher in all three androgen-independent cell lines compared to LNCaP cells. Thus in three models of aggressive human prostate cancer, hyperactivity of Rac1 corresponds to suppressed levels of p21. These results are unique in describing a role for Rac1 in p21 regulation and may implicate the Rac1 signaling pathway as a potential therapeutic target for controlling prostate cancer cell growth following progression to androgen independence.
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PMID:Deregulation of the Rho GTPase, Rac1, suppresses cyclin-dependent kinase inhibitor p21(CIP1) levels in androgen-independent human prostate cancer cells. 1507 74

Mitochondrial aconitase (mACON) is regarded as the key enzyme for citrate oxidation in human prostatic epithelial cells. The results of RT-PCR and immunoblot assays indicated that human prostatic carcinoma cells (PC-3 cells) express the long-form of the prolactin receptor. In vitro studies determined that prolactin upregulates mACON enzymatic activity and cell proliferation of PC-3 cells. Immunoblot assay revealed that prolactin treatments increase the gene expression of mACON. Transient gene expression assay indicated that the regulation by prolactin of mACON gene expression depends on the presence of the cyclic adenosine 3',5'-monosphosphate (cAMP) response element on the promoter of the mACON gene. Both prolactin and dibutyryl-cAMP doubled the promoter activity of the mACON gene; however, adding H-89, a specific protein kinase A inhibitor, suppressed the prolactin response. The intracellular cAMP levels, but not the cGMP levels, increased after treatment with prolactin. This study showed that prolactin regulates the expression of the mACON gene via the cAMP signal pathway in human prostatic carcinoma cells.
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PMID:Cyclic adenosine 3',5'-monosphosphate mediate prolactin regulation of mitochondrial aconitase in human prostate carcinoma cells. 1514 35

Cdc25A and Cdc25B dual-specificity phosphatases are key regulators of cell cycle transition and proliferation. They have oncogenic properties and are overexpressed in many human tumors. Because selective Cdc25 phosphatase inhibitors would be valuable biological tools and possible therapeutic agents, we have assayed a small molecule library for in vitro inhibition of Cdc25. We now report the identification of two new structurally distinct classes of Cdc25 inhibitors with cellular activity. The cyclopentaquinoline 3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-4,8-dicarboxylic acid (5661118) and the naphthofurandione 3-benzoyl-naphtho[1,2-b]furan-4,5-dione (5169131) had in vitro IC50 values of 2.5 to 11 microM against recombinant Cdc25 and were less potent inhibitors of other phosphatases. Unlike 5661118, 5169131 caused reversible inhibition of Cdc25B and displayed competitive inhibitor kinetics. No growth inhibitory activity was seen with 5661118, whereas 10 to 30 microM 5169131 caused G1/S and G2/M arrest. We also found that 5169131 inhibited human PC-3 prostate and MDA-MB-435 breast cancer cell proliferation. Concentration-dependent Tyr15 hyperphosphorylation was seen on cyclin-dependent kinase with a 1-h 5169131 treatment, consistent with Cdc25 inhibition. Cells resistant to DNA toposiomerase II inhibitors were as sensitive to 5169131 as parental cells, indicating that this quinone compound does not inhibit topoisomerase II in vivo. Molecular modeling was used to predict a potential interaction site between the inhibitor and Cdc25B and to provide insights as to the molecular origins of the experimental observations. Based on its kinetic profile and cellular activity, we suggest that 5169131 could be an excellent tool for further studies on the cellular roles of Cdc25.
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PMID:Discovery and characterization of novel small molecule inhibitors of human Cdc25B dual specificity phosphatase. 1523 69

We have investigated the effects of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a well known DNA alkylating agent, on the growth and cell cycle progression in human prostate carcinoma PC-3 and DU145 cells, which are lacking both p53 alleles and having mutated p53, respectively. It was found that MNNG could inhibit the cell growth in a dose-dependent manner, which was associated with dendrite-like morphological change and induction of apoptotic cell death. Flow cytometry showed that MNNG could cause an arrest at the G2/M phase of the cell cycle, which is closely correlated to inhibition of cyclin-dependent kinase (Cdk) 2 and Cdc2 kinase activities. Furthermore, this compound induced Cdk inhibitor p21WAF1/CIP1 expression at both the transcription and protein levels in a p53-independent manner. MNNG also activated the reporter construct of a p21 promoter. Present results indicate that the up-regulation of p21 by MNNG is likely responsible for the inhibition of Cdks kinase activity rather than the down-regulation of cyclins and Cdks expression.
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PMID:Induction of apoptosis and G2/M arrest by N-methyl-N'-nitro-N-nitrosoguanidine in human prostate carcinoma cells. 1536 80

Endocannabinoids have been implicated in cancer. Increasing endogenous 2-arachidonoylglycerol (2-AG) by blocking its metabolism inhibits invasion of androgen-independent prostate cancer (PC-3 and DU-145) cells. Noladin ether (a stable 2-AG analog) and exogenous CB1 receptor agonists possess similar effects. Conversely, reducing endogenous 2-AG by inhibiting its synthesis or blocking its binding to CB1 receptors with antagonists increases the cell invasion. 2-AG and noladin ether decrease protein kinase A activity in these cells, indicating coupling of the CB1 receptor to downstream effectors. The results suggest that cellular 2-AG, acting through the CB1 receptor, is an endogenous inhibitor of invasive prostate cancer cells.
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PMID:2-arachidonoylglycerol: a novel inhibitor of androgen-independent prostate cancer cell invasion. 1560 40

Evidence suggests that the angiogenic endothelium represents an important target through which celecoxib mediates in vivo antitumor effects. Nevertheless, the pharmacologic basis for celecoxib-caused growth inhibition in endothelial cells in vitro remains to be defined. Previously, we showed that celecoxib-induced apoptosis in PC-3 prostate cancer cells was mediated in part through the inhibition of 3-phosphoinositide-dependent kinase-1/Akt signaling. Our present findings show that celecoxib inhibits the growth of human umbilical vein endothelial cells (HUVEC) with pharmacologic profiles reminiscent of those of PC-3 cells. The underlying antiproliferative mechanism, however, may differ between these two cell types considering differences in the functional status of many tumor suppressors, including PTEN, p53, and retinoblastoma, all of which play integral roles in regulating cell cycle progression and survival. From a mechanistic perspective, the genomic integrity of the HUVEC system presents a vastly different intracellular context to examine how celecoxib acts to induce growth inhibition. Here, we obtain evidence that the antiproliferative effects of celecoxib and its close, cyclooxygenase-2-inactive analogue 4-[5-(2,5-dimethylphenyl)-3(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (DMC) in HUVECs at pharmacologically attainable concentrations (10-20 micromol/L) are attributable to the inhibition of phosphoinositide-dependent kinase-1/Akt signaling and cyclin-dependent kinase. Especially, celecoxib- and DMC-mediated G1 arrest is associated with attenuated retinoblastoma phosphorylation through the inhibition of multiple cyclin-dependent kinases (IC50, 10-35 micromol/L). Moreover, both celecoxib and DMC reduce neovascularization in the chicken chorioallantoic membrane assay, suggesting the involvement of a cyclooxygenase-2-independent mechanism in the in vivo antiangiogenic effects of celecoxib.
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PMID:Growth inhibitory effects of celecoxib in human umbilical vein endothelial cells are mediated through G1 arrest via multiple signaling mechanisms. 1563 61

An increase in the activity of mitogen-activated protein kinase (MAPK) has been correlated with the progression of prostate cancer to advanced disease in humans. The serine/threonine protein kinase p90-kDa ribosomal S6 kinase (RSK) is an important downstream effector of MAPK but its role in prostate cancer has not previously been examined. Increasing RSK isoform 2 (RSK2) levels in the human prostate cancer line, LNCaP, enhanced prostate-specific antigen (PSA) expression, an important diagnostic marker for prostate cancer, whereas inhibiting RSK activity using a RSK-specific inhibitor, 3Ac-SL0101, decreased PSA expression. The RSK2 regulation of PSA expression occurred via a mechanism involving both RSK2 kinase activity and its ability to associate with the coactivator, p300. RNA interference of the androgen receptor (AR) showed that the AR was important in the RSK2-mediated increase in PSA expression. RSK levels are higher in approximately 50% of human prostate cancers compared with normal prostate tissue, which suggests that increased RSK levels may participate in the rise in PSA expression that occurs in prostate cancer. Furthermore, 3Ac-SL0101 inhibited proliferation of the LNCaP line and the androgen-independent human prostate cancer line, PC-3. These results suggest that proliferation of some prostate cancer cells is dependent on RSK activity and support the hypothesis that RSK may be an important chemotherapeutic target for prostate cancer.
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PMID:The serine/threonine protein kinase, p90 ribosomal S6 kinase, is an important regulator of prostate cancer cell proliferation. 1583 40

Prostate cancer metastasizes predominantly to bone, where it induces osteoblastic lesions. Paracrine factors secreted by the metastatic cancer cells are thought to mediate these events. We previously isolated a novel bone metastasis-related factor (MDA-BF-1) from bone marrow aspirate samples from patients with prostate cancer and bone metastasis, and found that this factor stimulated osteoblast differentiation, possibly by interacting with a receptor on the osteoblasts. Identifying this putative MDA-BF-1 receptor biochemically requires the expression of MDA-BF-1 for receptor binding assays and for the preparation of a ligand-affinity column. We tagged MDA-BF-1 with a peptide containing a protein kinase A phosphorylation site plus a 7-histidine sequence to facilitate the labeling of MDA-BF-1 for receptor binding assay and the binding of MDA-BF-1 to an immobilized metal affinity column. The recombinant MDA-BF-1 protein (MDA-BF1-kinase-his) was expressed in Sf9 cells using a baculovirus expression system. About 0.8 mg of purified MDA-BF1-kinase-his protein was obtained from 4 x 10(8) Sf9 cells. MDA-BF1-kinase-his can be phosphorylated by PKA with a specific activity around 10(5)cpm/mug protein. Receptor binding assays using this (32)P-labeled MDA-BF-1 showed that MDA-BF-1 bound to membranes prepared from Saos-2, an osteosarcoma cell line, and C2C12, a mouse pluripotent mesenchymal precursor cell line that can be induced to become osteoblast by BMP-2. In contrast, MDA-BF-1 did not bind to membranes from PC-3 human prostate cancer cells or HEK293 human embryonic kidney cells. These observations suggest that the MDA-BF-1 receptor is expressed in cells of osteoblastic lineage. In addition to its use as a ligand for receptor binding assays, a ligand affinity column can be prepared by binding MDA-BF1-kinase-his to an IMAC for the purification of MDA-BF-1 receptor.
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PMID:Expression of recombinant MDA-BF-1 with a kinase recognition site and a 7-histidine tag for receptor binding and purification. 1591 29


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