5-alpha-reductase: 2013-06-16

2013年6月22日星期六

Antiangiogenic agents in advanced, persistent or recurrent endometrial cancer: a novel treatment option.

Antiangiogenic agents in advanced, persistent or recurrent endometrial cancer: a novel treatment option.

Gynecol Endocrinol. 2013 Jun 14;

Authors: Gadducci A, Sergiampietri C, Guiggi I

Abstract
Abstract The limited efficacy of endocrine therapy and chemotherapy has stimulated several researches aimed to detect novel molecularly target therapies for advanced, persistent or recurrent endometrial cancer. Prior attempts to block vascular endothelial growth factor (VEGF) with sunitinib, sorafenib and thalidomide have obtained disappointing results. Bevacizumab has shown a promising activity in a phase II study. The percentages of patients with progression-free survival ?6 months were similar for endometrioid (35%) and serous carcinoma (36%), but the number of cases was too small to assess the relevance of histological type for response to bevacizumab. In a phase II study, aflibercept was administered every 2 weeks to women with recurrent or persistent disease after chemotherapy. Forty-one percent of the patients were progression-free at 6 months, but 32% of the women had been removed from study because of toxicity. The detection of activating mutations of Fibroblast Growth Factor Receptor (FGFR)-2 in primary endometrial carcinoma has generated a new avenue for the development of molecularly target agents. Dovitinib, a tyrosine kinase inhibitor targeting both VEGF receptor (VEGFR) and FGFRs, is under clinical investigation in different malignancies including endometrial cancer.

PMID: 23767831 [PubMed - as supplied by publisher]

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Antiangiogenic agents in advanced, persistent or recurrent endometrial cancer: a novel treatment option.

Antiangiogenic agents in advanced, persistent or recurrent endometrial cancer: a novel treatment option.

Gynecol Endocrinol. 2013 Jun 14;

Authors: Gadducci A, Sergiampietri C, Guiggi I

PMID: 23767831 [PubMed - as supplied by publisher]

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Antiretroviral activity of protease inhibitors against Toxoplasma gondii.

Antiretroviral activity of protease inhibitors against Toxoplasma gondii.

Rev Inst Med Trop Sao Paulo. 2013 Jan-Feb;55(1):65-7

Authors: Monzote L, Rodr�guez M, Alfonso Y, Cox R

Abstract
The introduction of highly active antiretroviral therapy (HAART) has caused a marked reduction in the occurrence and severity of parasitic infections, including the toxoplasmic encephalitis (TE). These changes have been attributed to the restoration of cell-mediated immunity. This study was developed to examine the activity of six antiretroviral protease inhibitors (API) on Toxoplasma gondii tachyzoites. The six API showed anti-Toxoplasma activity, with IC50 value between 1.4 and 6.6 �g/mL. Further studies at the molecular level should be performed to clarify if the use of API could be beneficial or not for AIDS patients with TE.

PMID: 23328729 [PubMed - indexed for MEDLINE]

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Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial.

Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial.

Circulation. 2013 Feb 5;127(5):634-40

Authors: Dans AL, Connolly SJ, Wallentin L, Yang S, Nakamya J, Brueckmann M, Ezekowitz M, Oldgren J, Eikelboom JW, Reilly PA, Yusuf S

Abstract
BACKGROUND: The Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial showed that dabigatran etexilate 150 mg BID was superior and dabigatran etexilate 110 mg BID was noninferior to warfarin in preventing stroke and systemic embolism in patients with atrial fibrillation. In this subgroup analysis, we assess the efficacy and safety of dabigatran in patients who did and did not receive concomitant antiplatelets.
METHODS AND RESULTS: All comparisons used a Cox proportional hazards model with adjustments made for risk factors for bleeding. A time-dependent analysis was performed when comparing patients with concomitant antiplatelets with those without. Of 18 113 patients, 6952 (38.4%) received concomitant aspirin or clopidogrel at some time during the study. Dabigatran etexilate 110 mg BID was noninferior to warfarin in reducing stroke and systemic embolism, whether patients received antiplatelets (hazard ratio [HR], 0.93; 95% confidence interval [95% CI], 0.70-1.25) or not (HR, 0.87; 95% CI, 0.66-1.15; interaction P=0.738). There were fewer major bleeds than warfarin in both subgroups (HR, 0.82; 95% CI, 0.67-1.00 for patients who used antiplatelets; HR, 0.79; 95% CI, 0.64-0.96 for patients who did not; interaction P=0.794). Dabigatran etexilate 150 mg BID reduced the primary outcome of stroke and systemic embolism in comparison with warfarin. This effect seemed attenuated among patients who used antiplatelets (HR, 0.80; 95% CI, 0.59-1.08) in comparison with those who did not (HR, 0.52; 95% CI, 0.38-0.72; P for interaction=0.058). Major bleeding was similar to warfarin regardless of antiplatelet use (HR, 0.93; 95% CI, 0.76-1.12 for patients who used antiplatelets; HR, 0.94; 95% CI, 0.78-1.15 for patients who did not; P for interaction=0.875). In the time-dependent analysis, concomitant use of a single antiplatelet seemed to increase the risk of major bleeding (HR, 1.60; 95% CI, 1.42-1.82). Dual antiplatelet seemed to increased this even more (HR, 2.31; 95% CI, 1.79-2.98). The absolute risks were lowest on dabigatran etexilate 110 mg BID in comparison with dabigatran etexilate 150 mg BID or warfarin.
CONCLUSIONS: Concomitant antiplatelet drugs appeared to increase the risk for major bleeding in RE-LY without affecting the advantages of dabigatran over warfarin. Choosing between dabigatran etexilate 110 mg BID and dabigatran etexilate 150 mg BID requires a careful assessment of characteristics that influence the balance between benefit and harm.
CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00262600.

PMID: 23271794 [PubMed - indexed for MEDLINE]

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2013年6月21日星期五

Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection.

Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection.

J Clin Oncol. 2013 Apr 20;31(12):1514-21

Authors: Tsan YT, Lee CH, Ho WC, Lin MH, Wang JD, Chen PC

Abstract
PURPOSE: Statins may have protective effects against cancer, but no studies have focused on their effects in patients with chronic hepatitis C virus (HCV) infection. The purpose of this study was to investigate the association between use of statins and risk of hepatocellular carcinoma (HCC) in HCV-infected patients.
PATIENTS AND METHODS: Ours was a population-based cohort study of 260,864 HCV-infected patients enrolled in the Taiwan National Health Insurance Research Database since January 1, 1999, and observed through December 31, 2010. Cox proportional hazards regression with time-dependent covariates for drug exposures was employed to evaluate the association between statin use and HCC risk.
RESULTS: There were 27,883 cases of HCC in the HCV cohort during a follow-up period of 2,792,016.6 person-years. Among the 35,023 patients using statins (defined as ? 28 cumulative defined daily doses [cDDDs]), 1,378 had HCC. Among the 225,841 patients not using statins (< 28 cDDDs), 26,505 were diagnosed with HCC. A dose-response relationship between statin use and HCC risk was observed. The adjusted hazard ratios were 0.66 (95% CI, 0.59 to 0.74), 0.47 (95% CI, 0.40 to 0.56), and 0.33 (95% CI, 0.25 to 0.42) for patients with 28 to 89, 90 to 180, and > 180 cDDDs per year, respectively, relative to nonusers. The reduction in risk also demonstrated a progressive duration-response relationship in patients with ? 28 cDDDs per year when compared with nonusers.
CONCLUSION: Among patients with HCV infection, statin use was associated with reduced risk of HCC. Further research is needed to elucidate the mechanism responsible for this effect.

PMID: 23509319 [PubMed - indexed for MEDLINE]

CASPASE INHIBITOR selleckchem

Seminars in clinical pharmacology: an introduction to MET inhibitors for the medical oncologist.

Seminars in clinical pharmacology: an introduction to MET inhibitors for the medical oncologist.

Ann Oncol. 2013 Jan;24(1):14-20

Authors: Fasolo A, Sessa C, Gianni L, Broggini M

Abstract
MET is a tyrosine kinase receptor for hepatocyte growth factor (HGF), primarily expressed on epithelial cells; the activation of MET induces several biological responses relevant for the development and growth of many human cancers. Several human malignancies present altered expression of MET and this is usually associated with poor prognosis and aggressive phenotype. The majority of MET inhibitors in clinical development target directly the receptor through the use of monoclonal antibodies (MAbs) or through small molecule inhibitors of MET kinase activity; small molecule inhibitors are very potent but less specific than MAbs. MET inhibitors are of great clinical interest because of the extensive crosstalk of the HGF/MET axis with many other signaling pathways, including growth factor-dependent pathways (like PI3K/AKT/mTOR,RAS/RAF/ERK) and vascular endothelial growth factor (VEGF) axis. In preclinical studies, the treatment with MET inhibitors could prevent or reverse resistance to inhibitors of growth factor-dependent signaling; this hypothesis is currently tested in phase III trials with anti-epidermal growth factor receptor (EGFR) inhibitors in non-small-cell lung cancer (NSCLC). Based on preclinical and preliminary clinical results, a rational strategy for the clinical development of MET antagonists should include a selection of the tumors with MET overexpression, the identification of prognostic/predictive biomarkers, the evaluation of combinations with anti-VEGF compounds.

PMID: 23110808 [PubMed - indexed for MEDLINE]

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Seminars in clinical pharmacology: an introduction to MET inhibitors for the medical oncologist.

Seminars in clinical pharmacology: an introduction to MET inhibitors for the medical oncologist.

Ann Oncol. 2013 Jan;24(1):14-20

Authors: Fasolo A, Sessa C, Gianni L, Broggini M

PMID: 23110808 [PubMed - indexed for MEDLINE]

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Cancer cell resistance to aurora kinase inhibitors: identification of novel targets for cancer therapy.

Cancer cell resistance to aurora kinase inhibitors: identification of novel targets for cancer therapy.

J Proteome Res. 2013 Jan 4;12(1):455-69

Authors: Hrabakova R, Kollareddy M, Tyleckova J, Halada P, Hajduch M, Gadher SJ, Kovarova H

Abstract
Drug resistance is the major obstacle to successful cancer therapy. Our study focuses on resistance to Aurora kinase inhibitors tested as anti-cancer drugs in clinical trials. We have used 2D electrophoresis in the pH ranges of 4-7 and 6-11 followed by protein identification using MALDI-TOF/TOF to compare the protein composition of HCT116 colon cancer cells either sensitive to CYC116 and ZM447439 inhibitors or resistant toward these drugs. The analysis also included p53(+/+) and p53(-/-) phenotypes of HCT116 cells. Our findings demonstrate that platelet-activating factor acetylhydrolase and GTP-binding nuclear protein Ran contribute to the development of resistance to ZM447439 only where resistance is related to p53. On the other hand, serine hydroxymethyltransferase was found to promote the tumor growth in cells resistant to CYC116 without the influence of p53. Computer modeling of interaction networks highlighted a direct link of the p53-independent mechanism of resistance to CYC116 with autophagy. Importantly, serine hydroxymethyltransferase, serpin B5, and calretinin represent the target proteins that may help overcome resistance in combination therapies. In addition, serpin B5 and calretinin appear to be candidate biomarkers that may be accessible in patients for monitoring of cancer therapy with ease.

PMID: 23151231 [PubMed - indexed for MEDLINE]

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Porcine hemagglutinating encephalomyelitis virus induces apoptosis in a porcine kidney cell line via caspase-dependent pathways.

Porcine hemagglutinating encephalomyelitis virus induces apoptosis in a porcine kidney cell line via caspase-dependent pathways.

Virus Res. 2013 Jun 12;

Authors: Lan Y, Zhao K, Wang G, Dong B, Zhao J, Tang B, Lu H, Gao W, Chang L, Jin Z, Gao F, He W

Abstract
Porcine hemagglutinating encephalomyelitis is an acute, highly contagious disease in piglets that is caused by the porcine hemagglutinating encephalomyelitis virus (PHEV). However, the pathogenesis of PHEV and the relationship between PHEV and the host cells are not fully understood. In this study, we investigated whether the PHEV-induced cytopathic effect (CPE) was caused by apoptosis. Replication of PHEV in a porcine kidney-derived cell line (PK-15 cells) caused an extensive CPE, leading to the destruction of the entire monolayer and the death of the infected cells. Staining with Hoechst 33342 revealed morphological changes in the nuclei and chromatin fragmentation. In addition, PHEV caused DNA fragmentation detectable by agarose gel electrophoresis 48h post-infection, increasing with the incubation time. The percentage of apoptotic cells increased with the incubation time and reached a maximum at 96h post-infection, as determined using flow cytometry and fluorescence microscopy of cells that were stained with annexin V-FITC and propidium iodide (PI). Moreover, as is commonly observed for coronavirus infections of other animals, the activities of the effecter caspase, caspase-3, and the initiator caspases, caspase-8 and caspase-9, which are representative factors in the death receptor-mediated apoptotic pathway and the mitochondrial apoptotic pathway, respectively, were increased in PHEV-infected PK-15 cells. Moreover, the tripeptide pan-ICE (caspase) inhibitor Z-VAD-FMK blocked PHEV-induced apoptosis but did not have an effect on virus production by 96h post-infection. These results suggested that PHEV induces apoptosis in PK-15 cells via a caspase-dependent pathway. Apoptotic death of infected cells is detrimental to animals because it causes cell and tissue destruction. Although the pathological characteristics of PHEV are largely unknown, apoptosis may be the pathological basis of the lesions resulting from PHEV infection.

PMID: 23770152 [PubMed - as supplied by publisher]

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2013年6月20日星期四

Death receptor 5 agonistic antibody PRO95780: preclinical pharmacokinetics and concentration-effect relationship support clinical dose and regimen selection.

Death receptor 5 agonistic antibody PRO95780: preclinical pharmacokinetics and concentration-effect relationship support clinical dose and regimen selection.

Cancer Chemother Pharmacol. 2013 Jun 16;

Authors: Xiang H, Reyes AE, Eppler S, Kelley S, Damico-Beyer LA

Abstract
PURPOSE: PRO95780, a human monoclonal antibody (mAb) against death receptor 5 (DR5/TRAIL-R2/TNFRSF10B), was developed for the treatment for cancer. Our objective was to characterize pharmacokinetics (PK) in mice, rats, and cynomolgus monkeys and concentration-effect relationships of PRO95780 in xenograft mouse models of human cancers; this would guide the selection of dose and regimen for clinical trials. METHODS: The PK profiles were determined in mice, rats, and cynomolgus monkeys. Three xenograft models with a wide range of in vitro sensitivities to PRO95780 were selected for efficacy studies. Tumoristatic serum concentrations (TSCs) were determined using PK/pharmacodynamic (PD) modeling with tumor growth as a PD endpoint. A species-invariant time PK scaling method was employed to estimate disposition in humans using PK data in cynomolgus monkeys. Furthermore, the predicted human PK parameters were used to estimate dose and regimen to achieve TSC observed in mice at the steady-state trough concentrations (C trough ss) in the clinic. RESULTS: Linear PK was observed across species. A serum concentration of 22�?g/mL was identified to be the target TSC in mice. A dose of 10�mg/kg administered once every 2�weeks (Q2W) was predicted to achieve a TSC at C trough ss in 95�% of patients. CONCLUSIONS: PRO95780 has linear PK in mice, rats, and monkeys. Estimated TSCs varied among different xenograft models. A projected target dose in humans is achievable for Q2W administration within the dose range used for other commercial mAbs.

PMID: 23771513 [PubMed - as supplied by publisher]

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Biphasic Modulation of NOS Expression, Protein and Nitrite Products by Hydroxocobalamin Underlies Its Protective Effect in Endotoxemic Shock: Downstream Regulation of COX-2, IL-1?, TNF-?, IL-6, and HMGB1 Expression.

Biphasic Modulation of NOS Expression, Protein and Nitrite Products by Hydroxocobalamin Underlies Its Protective Effect in Endotoxemic Shock: Downstream Regulation of COX-2, IL-1?, TNF-?, IL-6, and HMGB1 Expression.

Mediators Inflamm. 2013;2013:741804

Authors: Sampaio AL, Dalli J, Brancaleone V, D'Acquisto F, Perretti M, Wheatley C

Abstract
Background. NOS/(?)NO inhibitors are potential therapeutics for sepsis, yet they increase clinical mortality. However, there has been no in vivo investigation of the (in vitro) (?)NO scavenger, cobalamin's (Cbl) endogenous effects on NOS/(?)NO/inflammatory mediators during the immune response to sepsis. Methods. We used quantitative polymerase chain reaction (qPCR), ELISA, Western blot, and NOS Griess assays, in a C57BL/6 mouse, acute endotoxaemia model. Results. During the immune response, pro-inflammatory phase, parenteral hydroxocobalamin (HOCbl) treatment partially inhibits hepatic, but not lung, iNOS mRNA and promotes lung eNOS mRNA, but attenuates the LPS hepatic rise in eNOS mRNA, whilst paradoxically promoting high iNOS/eNOS protein translation, but relatively moderate (?)NO production. HOCbl/NOS/(?)NO regulation is reciprocally associated with lower 4?h expression of TNF-?, IL-1 ? , COX-2, and lower circulating TNF-?, but not IL-6. In resolution, 24?h after LPS, HOCbl completely abrogates a major late mediator of sepsis mortality, high mobility group box 1 (HMGB1) mRNA, inhibits iNOS mRNA, and attenuates LPS-induced hepatic inhibition of eNOS mRNA, whilst showing increased, but still moderate, NOS activity, relative to LPS only. experiments (LPS+D-Galactosamine) HOCbl afforded significant, dose-dependent protection in mice Conclusions. HOCbl produces a complex, time- and organ-dependent, selective regulation of NOS/(?)NO during endotoxaemia, corollary regulation of downstream inflammatory mediators, and increased survival. This merits clinical evaluation.

PMID: 23781123 [PubMed - in process]

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DNA damage-induced inhibition of rRNA synthesis by DNA-PK and PARP-1.

DNA damage-induced inhibition of rRNA synthesis by DNA-PK and PARP-1.

Nucleic Acids Res. 2013 Jun 17;

Authors: Calkins AS, Iglehart JD, Lazaro JB

Abstract
RNA synthesis and DNA replication cease after DNA damage. We studied RNA synthesis using an in situ run-on assay and found ribosomal RNA (rRNA) synthesis was inhibited 24 h after UV light, gamma radiation or DNA cross-linking by cisplatin in human cells. Cisplatin led to accumulation of cells in S phase. Inhibition of the DNA repair proteins DNA-dependent protein kinase (DNA-PK) or poly(ADP-ribose) polymerase 1 (PARP-1) prevented the DNA damage-induced block of rRNA synthesis. However, DNA-PK and PARP-1 inhibition did not prevent the cisplatin-induced arrest of cell cycle in S phase, nor did it induce de novo BrdU incorporation. Loss of DNA-PK function prevented activation of PARP-1 and its recruitment to chromatin in damaged cells, suggesting regulation of PARP-1 by DNA-PK within a pathway of DNA repair. From these results, we propose a sequential activation of DNA-PK and PARP-1 in cells arrested in S phase by DNA damage causes the interruption of rRNA synthesis after DNA damage.

PMID: 23775790 [PubMed - as supplied by publisher]

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DNA damage-induced inhibition of rRNA synthesis by DNA-PK and PARP-1.

DNA damage-induced inhibition of rRNA synthesis by DNA-PK and PARP-1.

Nucleic Acids Res. 2013 Jun 17;

Authors: Calkins AS, Iglehart JD, Lazaro JB

PMID: 23775790 [PubMed - as supplied by publisher]

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2013年6月19日星期三

Local requirement of the Drosophila insulin binding protein Imp-L2 in coordinating developmental progression with nutritional conditions.

Local requirement of the Drosophila insulin binding protein Imp-L2 in coordinating developmental progression with nutritional conditions.

Dev Biol. 2013 Jun 14;

Authors: Sarraf-Zadeh L, Christen S, Sauer U, Cognigni P, Miguel-Aliaga I, Stocker H, K�hler K, Hafen E

Abstract
In Drosophila, growth takes place during the larval stages until the formation of the pupa. Starvation delays pupariation to allow prolonged feeding, ensuring that the animal reaches an appropriate size to form a fertile adult. Pupariation is induced by a peak of the steroid hormone ecdysone produced by the prothoracic gland (PG) after larvae have reached a certain body mass. Local downregulation of the insulin/insulin-like growth factor signaling (IIS) activity in the PG interferes with ecdysone production, indicating that IIS activity in the PG couples the nutritional state to development. However, the underlying mechanism is not well understood. In this study we show that the secreted Imaginal morphogenesis protein-Late 2 (Imp-L2), a growth inhibitor in Drosophila, is involved in this process. Imp-L2 inhibits the activity of the Drosophila insulin-like peptides by direct binding and is expressed by specific cells in the brain, the ring gland, the gut and the fat body. We demonstrate that Imp-L2 is required to regulate and adapt developmental timing to nutritional conditions by regulating IIS activity in the PG. Increasing Imp-L2 expression at its endogenous sites using an Imp-L2-Gal4 driver delays pupariation, while Imp-L2 mutants exhibit a slight acceleration of development. These effects are strongly enhanced by starvation and are accompanied by massive alterations of ecdysone production resulting most likely from increased Imp-L2 production by neurons directly contacting the PG and not from elevated Imp-L2 levels in the hemolymph. Taken together our results suggest that Imp-L2-expressing neurons sense the nutritional state of Drosophila larvae and coordinate dietary information and ecdysone production to adjust developmental timing under starvation conditions.

PMID: 23773803 [PubMed - as supplied by publisher]

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Impact of celecoxib on soluble intercellular adhesion molecule-1 and soluble e-cadherin concentrations in human colon cancer cell line cultures exposed to phytic acid and TNF-alpha.

Impact of celecoxib on soluble intercellular adhesion molecule-1 and soluble e-cadherin concentrations in human colon cancer cell line cultures exposed to phytic acid and TNF-alpha.

Acta Pol Pharm. 2012 Nov-Dec;69(6):1283-90

Authors: Parfiniewicz B, Pendzich J, Gruchlik A, Hollek A, Weglarz L

Abstract
Soluble adhesion molecules such as soluble intercellular adhesion molecules-1 (sICAM-1) and soluble E-cadherin (sE-cadherin) play important role in tumor invasion and the development of metastasis. It was observed that their concentrations in body fluids of patients with colon cancer were elevated. Celecoxib, a selective inhibitor of cyclooxygenase-2 (COX-2) besides its analgesic, anti-inflammatory, and antipyretic activity is able to inhibit development of colon cancer and reduce risk of metastasis. The additional factors, e.g., dietary components in colon cancer, may influence therapeutic effect of drugs, such as cytokines. TNF-alpha (tumor necrosis factor - alpha) is a cytokine, which concentration significantly increases in serum of patients with inflammatory and cancer diseases. The latest studies demonstrate, that phytic acid (IP6), a myo-inositol derivative, abundantly present in high-fiber diets could substantially reduce colon cancer incidence. The aim of the present study was to evaluate the influence of celecoxib on sICAM-1 and sE-cadherin concentrations in transformed epithelial colon cell cultures simultaneously exposed to IP6 and TNF-alpha. Additionally, the adhesion of the exposed cells to collagen I was assessed. HT-29 and Caco-2 cells were cultured in the presence of 50 ng/mL celecoxib, 1.0 mM IP6, and 100 ng/mL TNF-alpha, and their combination: TNF-alpha plus IP6, TNF-alpha plus celecoxib, IP6 plus celecoxib, and TNF-alpha with celecoxib plus IP6, for 96 h. Nonexposed cell line cultures served as controls. Concentrations of sICAM-1 and sE-cadherin were measured in the culture medium by enzyme-linked immunosorbent assay (ELISA) using Quantikine - Human sICAM-1/CD54 Immunoassay and Quantikine-Human sE-Cadherin Immunoassay. All the results obtained were expressed as ng per mL. In the adhesion assay, the cells were incubated with IP6 (0.5, 1.0 and 2.0 mM), TNF-alpha (100 ng/mL), celecoxib (50 ng/mL) and their combination for 90 min. Fluorescence values 480 nm/530 nm reflected concentrations of DNA in cells attached to collagen I. The obtained results indicate that celecoxib (50 ng/mL), the selective COX-2 inhibitor, reduces significantly sICAM-1 and sE-cadherin concentrations in HT-29 and Caco-2 transformed human epithelial colorectal cell line cultures co-treated with IP6 (1.0 mM) and TNF-alpha (100 ng/mL). A decrease of cells adhesion property to collagen I was observed under the influence of 50 ng/mL celecoxib on cell cultures exposed to 1.0 or 2.0 mM IP6 and 1.0 or 2.0 mM IP6 plus 100 ng/mL TNF-alpha.

PMID: 23285691 [PubMed - in process]

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Impact of celecoxib on soluble intercellular adhesion molecule-1 and soluble e-cadherin concentrations in human colon cancer cell line cultures exposed to phytic acid and TNF-alpha.

Impact of celecoxib on soluble intercellular adhesion molecule-1 and soluble e-cadherin concentrations in human colon cancer cell line cultures exposed to phytic acid and TNF-alpha.

Acta Pol Pharm. 2012 Nov-Dec;69(6):1283-90

Authors: Parfiniewicz B, Pendzich J, Gruchlik A, Hollek A, Weglarz L

PMID: 23285691 [PubMed - in process]

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Comparative antioxidant effects of lycopene, apo-10'-lycopenoic acid and apo-14'-lycopenoic acid in human macrophages exposed to H2O2 and cigarette smoke extract.

Comparative antioxidant effects of lycopene, apo-10'-lycopenoic acid and apo-14'-lycopenoic acid in human macrophages exposed to H2O2 and cigarette smoke extract.

Food Chem Toxicol. 2013 Jan;51:71-9

Authors: Catalano A, Simone RE, Cittadini A, Reynaud E, Caris-Veyrat C, Palozza P

Abstract
Much of the beneficial effects of tomato lycopene in the prevention of chronic diseases has been attributed to its antioxidant properties, which could be mediated by its metabolites and/or oxidation products. However, the biological functions of these lycopene derivatives remain still unknown. In the present study, we evaluated and compared the antioxidant efficacy of the lycopene eccentric cleavage products apo-10'-lycopenoic acid and apo-14'-lycopenoic acid in counteracting the oxidative effects of H(2)O(2) and cigarette smoke extract (CSE) in THP-1 macrophages. Both apo-10'-lycopenoic acid and apo-14'-lycopenoic acid were able to inhibit spontaneous and H(2)O(2)-induced ROS production in a dose-dependent manner. Such an effect was accompanied by an inhibition of MAPK phosphorylation, by NF-?B inactivation, and by inhibition of hsp-70 and hsp-90 expressions. Both apo-lycopenoic acids also decreased CSE-induced ROS production, 8-OHdG formation and reduced the increase in NOX-4 and COX-2 expressions caused by CSE. However, in both the models of oxidative stress, apo-14'-lycopenoic acid was much more potent as an antioxidant than apo-10'-lycopenoic acid, showing antioxidant properties similar to lycopene. These data strongly suggest that apo-lycopenoic acids, and particularly apo-14'-lycopenoic acid, may mediate some of the antioxidant functions of lycopene in cells.

PMID: 22989703 [PubMed - in process]

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The decreased metastatic potential of rhabdomyosarcoma cells obtained through MET receptor downregulation and the induction of differentiation.

The decreased metastatic potential of rhabdomyosarcoma cells obtained through MET receptor downregulation and the induction of differentiation.

Cell Death Dis. 2013;4:e459

Authors: Miekus K, Lukasiewicz E, Jarocha D, Sekula M, Drabik G, Majka M

Abstract
Rhabdomyosarcoma (RMS) is the most common type of pediatric soft tissue sarcoma. The MET receptor has an important role in the biology of RMS, and its overexpression and hyperactivation correlate with the metastatic ability of RMS. Consequently, interfering with MET expression or functionality may constitute a sound strategy for reducing the progression and metastatic potential of RMS. Our study reveals that downregulation of the MET receptor leads to changes in the morphology of ARMS cell in vivo. Tumors acquire a spindle shape that is characteristic of muscle fibers. Inhibition of MET expression or function leads to (i) a decreased expression of the early myogenic marker MyoD, (ii) a decreased ability of ARMS cells to metastasize to bone marrow cavities, (iii) downregulation of CXCR4 receptor expression and (iv) a decreased migration of MET-depleted cells towards gradients of HGF and SDF-1. Finally, we demonstrate that in vitro differentiation of alveolar RMS cells decreases their metastatic behavior by reducing both the expression of the MET and CXCR4 receptors and their migratory response to HGF and SDF-1. These findings suggest that blockers of MET receptor function and inducers of RMS cells differentiation may be clinically useful for reducing the aggressiveness and metastatic potential of RMS and may have significant implications for its treatment.

PMID: 23328666 [PubMed - indexed for MEDLINE]

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2013年6月18日星期二

FGF Receptors: Cancer Biology and Therapeutics.

FGF Receptors: Cancer Biology and Therapeutics.

Med Res Rev. 2013 May 21;

Authors: Katoh M, Nakagama H

Abstract
Fibroblast growth factors (FGFs) are involved in a variety of cellular processes, such as stemness, proliferation, anti-apoptosis, drug resistance, and angiogenesis. Here, FGF signaling network, cancer genetics/genomics of FGF receptors (FGFRs), and FGFR-targeted therapeutics will be reviewed. FGF signaling to RAS-MAPK branch and canonical WNT signaling cascade mutually regulate transcription programming. FGF signaling to PI3K-AKT branch and Hedgehog, Notch, TGF?, and noncanonical WNT signaling cascades regulate epithelial-to-mesenchymal transition (EMT) and invasion. Gene amplification of FGFR1 occurs in lung cancer and estrogen receptor (ER)-positive breast cancer, and that of FGFR2 in diffuse-type gastric cancer and triple-negative breast cancer. Chromosomal translocation of FGFR1 occurs in the 8p11 myeloproliferative syndrome and alveolar rhabdomyosarcoma, as with FGFR3 in multiple myeloma and peripheral T-cell lymphoma. FGFR1 and FGFR3 genes are fused to neighboring TACC1 and TACC3 genes, respectively, due to interstitial deletions in glioblastoma multiforme. Missense mutations of FGFR2 are found in endometrial uterine cancer and melanoma, and similar FGFR3 mutations in invasive bladder tumors, and FGFR4 mutations in rhabdomyosarcoma. Dovitinib, Ki23057, ponatinib, and AZD4547 are orally bioavailable FGFR inhibitors, which have demonstrated striking effects in preclinical model experiments. Dovitinib, ponatinib, and AZD4547 are currently in clinical trial as anticancer drugs. Because there are multiple mechanisms of actions for FGFR inhibitors to overcome drug resistance, FGFR-targeted therapy is a promising strategy for the treatment of refractory cancer. Whole exome/transcriptome sequencing will be introduced to the clinical laboratory as the companion diagnostic platform facilitating patient selection for FGFR-targeted therapeutics in the era of personalized medicine.

PMID: 23696246 [PubMed - as supplied by publisher]

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FGF Receptors: Cancer Biology and Therapeutics.

FGF Receptors: Cancer Biology and Therapeutics.

Med Res Rev. 2013 May 21;

Authors: Katoh M, Nakagama H

PMID: 23696246 [PubMed - as supplied by publisher]

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Image-based high-throughput screening for inhibitors of angiogenesis.

Image-based high-throughput screening for inhibitors of angiogenesis.

Methods Mol Biol. 2013;931:139-51

Authors: Evensen L, Link W, Lorens JB

Abstract
Automated multicolor fluorescence microscopy facilitates high-throughput quantitation of cellular parameters of complex, organotypic systems. In vitro co-cultured vascular cells form capillary-like networks that model facets of angiogenesis, making it an attractive alternative for anti-angiogenic drug discovery. We have adapted this angiogenesis assay system to a high-throughput format to enable automated image-based high-throughput screening of live primary human vascular cell co-cultures with chemical libraries for anti-angiogenic drug discovery. Protocols are described for setup of a fluorescence-based co-culture assay, live cell image acquisition, image analysis of morphological parameters, and screening data handling.

PMID: 23027002 [PubMed - indexed for MEDLINE]

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Antioxidative, anti-inflammatory, and matrix metalloproteinase inhibitory activities of 20(S)-ginsenoside Rg3 in cultured mammalian cell lines.

Antioxidative, anti-inflammatory, and matrix metalloproteinase inhibitory activities of 20(S)-ginsenoside Rg3 in cultured mammalian cell lines.

Mol Biol Rep. 2013 Jan;40(1):269-79

Authors: Shin YM, Jung HJ, Choi WY, Lim CJ

Abstract
Ginsenoside Rg3 is one of ginsenosides that are the well-known bioactive principles of Panax ginseng. Among the two stereoisomeric forms of Rg3, 20(S)-ginsenoside Rg3 [20(S)-Rg3] is predominant. 20(S)-Rg3 is capable of suppressing the nitric oxide (NO), reactive oxygen species (ROS) and prostaglandin E2 (PGE2) productions induced by lipopolysaccharide (LPS) in RAW264.7 macrophage cells in a concentration-dependent manner. In the same stimulated macrophages, 20(S)-Rg3 was able to suppress matrix metalloproteinase-9 (MMP-9) activity and suppress cyclooxygenase-2 (COX-2) expression. It suppressed the production of some proinflammatory cytokines, such as TNF-?, IL-1? and IL-6, and the cell mobility enhanced by LPS in the macrophage cells. 20(S)-Rg3 displayed suppressive effect on the ROS level but not on the NO level, and down-regulating effect on MMP-9 but not on MMP-2 in non-stimulated HaCat keratinocytes. 20(S)-Rg3 also exhibited suppressive effect on the MMP-9 gelatinolytic activity enhanced in the HaCat keratinocytes stimulated with tumor necrosis factor-? (TNF-?), one of the major proinflammatory cytokines. However, 20(S)-Rg3 was not able to modulate the NO level even in the presence of TNF-?. Taken together, anti-inflammatory and related antioxidative and MMP-9 inhibitory activities of 20(S)-Rg3, the major stereoisomeric form of ginsenoside Rg3, are confirmed in macrophage and keratinocyte cell lines.

PMID: 23054007 [PubMed - indexed for MEDLINE]

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Current evidence on the relationship between three polymorphisms in the XRCC7 gene and cancer risk.

Current evidence on the relationship between three polymorphisms in the XRCC7 gene and cancer risk.

Mol Biol Rep. 2013 Jan;40(1):81-6

Authors: Zhang J, Wu XH, Gan Y

Abstract
Inconsistency of the association of polymorphisms of XRCC7 with cancer is noted. Three commonly studied XRCC7 polymorphisms including rs7003908 (T>G), rs7830743 (A>G), and rs10109984 (T>C) were selected to explore their association with risk of development of cancer by meta-analysis of published case-control studies. The results showed that no significant associations with cancer risk were found in any model in terms of rs7003908, rs7830743 and rs10109984 when all studies were pooled into the meta-analysis. But when stratified by cancer type, statistically significantly elevated cancer risk was only found in prostate cancer for rs7003908 (GG vs. TT: OR = 1.845, 95 % CI = 1.178-2.888; dominant model: OR = 1.423, 95 % CI = 1.050-1.929; recessive model: OR = 1.677, 95 % CI = 1.133-2.482). In the subgroup analysis by ethnicity or study design, no significantly increased risks were found for all three polymorphisms. This meta-analysis suggests that XRCC7 rs7003908 polymorphism may contribute to cancer susceptibility for prostate cancer, which is recommended to be included in future large-sample studies and functional assays.

PMID: 23108991 [PubMed - in process]

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2013年6月17日星期一

Molecular markers of response and resistance to EGFR inhibitors in head and neck cancers.

Molecular markers of response and resistance to EGFR inhibitors in head and neck cancers.

Front Biosci. 2013;18:520-42

Authors: Box C, Zimmermann M, Eccles S

Abstract
Receptor tyrosine kinases (RTK) are key targets for novel cancer therapeutics since they activate multiple oncogenic signalling pathways. Also, they are inherently 'druggable' due to their small ATP-dependent kinase domains (inhibitable by small molecules) and cell surface location which renders them accessible to monoclonal antibody-based therapies. The epidermal growth factor receptor (EGFR) is overexpressed in the majority of SCCHN cases and this review focuses primarily on the progress made in targeting the EGFR for the therapy of SCCHN by both small molecules and antibody-based therapies. We then discuss the overlapping and distinct molecular markers of response, innate or acquired resistance to each modality, and how these may be overcome. We also consider other RTKs overexpressed in this disease that may impact on responses and/or provide additional targets for combination therapy.

PMID: 23276940 [PubMed - in process]

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FGF Receptors: Cancer Biology and Therapeutics.

FGF Receptors: Cancer Biology and Therapeutics.

Med Res Rev. 2013 May 21;

Authors: Katoh M, Nakagama H

PMID: 23696246 [PubMed - as supplied by publisher]

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Image-based high-throughput screening for inhibitors of angiogenesis.

Image-based high-throughput screening for inhibitors of angiogenesis.

Methods Mol Biol. 2013;931:139-51

Authors: Evensen L, Link W, Lorens JB

PMID: 23027002 [PubMed - indexed for MEDLINE]

Caspase-8 inhibitor selleck chemical Caspase-9 inhibitor CASPASE INHIBITOR selleck chemical

FGF Receptors: Cancer Biology and Therapeutics.

FGF Receptors: Cancer Biology and Therapeutics.

Med Res Rev. 2013 May 21;

Authors: Katoh M, Nakagama H

PMID: 23696246 [PubMed - as supplied by publisher]

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Computational determination of the orientation of a heat repeat-like domain of DNA-PKcs.

Computational determination of the orientation of a heat repeat-like domain of DNA-PKcs.

Comput Biol Chem. 2013 Feb;42:1-4

Authors: Lindert S, Stewart PL, Meiler J

Abstract
DNA dependent protein kinase catalytic subunit (DNA-PKcs) is an important regulatory protein in non-homologous end joining a process used to repair DNA double strand breaks. Medium resolution structures both from cryoEM and X-ray crystallography show the general topology of the protein and positions of helices in parts of DNA-PKcs. EM-Fold, an algorithm developed for building protein models into medium resolution density maps has been used to generate models for the heat repeat-like "Ring structure" of the molecule. We were able to computationally corroborate placement of the N-terminus of the domain that supports a previously published hypothesis. Targeted experiments are suggested to test the model.

PMID: 23246775 [PubMed - in process]

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2013年6月16日星期日

Molecular markers of response and resistance to EGFR inhibitors in head and neck cancers.

Molecular markers of response and resistance to EGFR inhibitors in head and neck cancers.

Front Biosci. 2013;18:520-42

Authors: Box C, Zimmermann M, Eccles S

PMID: 23276940 [PubMed - in process]

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Image-based high-throughput screening for inhibitors of angiogenesis.

Image-based high-throughput screening for inhibitors of angiogenesis.

Methods Mol Biol. 2013;931:139-51

Authors: Evensen L, Link W, Lorens JB

PMID: 23027002 [PubMed - indexed for MEDLINE]

CASPASE INHIBITOR selleckchem selleck chemical Caspase-8 inhibitor

Traditionally used Veronica officinalis inhibits proinflammatory mediators via the NF-?B signalling pathway in a human lung cell line.

Traditionally used Veronica officinalis inhibits proinflammatory mediators via the NF-?B signalling pathway in a human lung cell line.

J Ethnopharmacol. 2013 Jan 9;145(1):118-26

Authors: Gr�ndemann C, Garcia-K�ufer M, Sauer B, Stangenberg E, K�ncz�l M, Merfort I, Zehl M, Huber R

Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Extracts from Veronica officinalis L. are traditionally used for the treatment of lung diseases; however, the effective compounds and the mode of action are still unknown.
AIM OF THE STUDY: Here we analyzed the effects of a standardized Veronica extract on genes expression and signalling protein production associated with the development of inflammatory lung diseases.
MATERIAL AND METHODS: The degranulation capacity of primary mast cells, as well as gene expression and release of inflammatory mediators from human lung epithelial cells (A549 cells) were analyzed in relation to the synthetic drugs azelastine and dexamethasone. Gene and protein expression of cyclooxygenase-2 were investigated by semi-quantitative RT-PCR and western blotting, respectively. The involvement of phosphorylated mitogen-activated protein kinases and NF-?B signaling in regulation of these molecules were characterized by western blotting and electrophoretic mobility shift assays. Characteristic extract components were identified by LC-MS and verminoside was quantified by HPLC analysis.
RESULTS: We demonstrated that Veronica officinalis has a small influence on the degranulation capacity of mast cells but rather inhibits gene and protein expression of the chemokine eotaxin in A549 lung epithelial cells, which is essential for recruitment of inflammatory-associated cells in lung diseases. Furthermore, release of the inflammatory mediator PGE(2) was diminished through inhibition of COX-2 expression via the NF-?B signaling pathway in TNF-?-activated A549 cells. Phytochemical analysis identified verproside and verminoside as the most abundant iridoid glycosides.
CONCLUSION: Our results are a contribution to explaining the observed anti-inflammatory effects of Veronica offcinalis extract on a molecular level. However, its clinical potency has at first to be proven in animals and subsequently in clinical trials.

PMID: 23142555 [PubMed - indexed for MEDLINE]

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Met synergizes with p53 loss to induce mammary tumors that possess features of claudin-low breast cancer.

Met synergizes with p53 loss to induce mammary tumors that possess features of claudin-low breast cancer.

Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):E1301-10

Authors: Knight JF, Lesurf R, Zhao H, Pinnaduwage D, Davis RR, Saleh SM, Zuo D, Naujokas MA, Chughtai N, Herschkowitz JI, Prat A, Mulligan AM, Muller WJ, Cardiff RD, Gregg JP, Andrulis IL, Hallett MT, Park M

Abstract
Triple-negative breast cancer (TNBC) accounts for ?20% of cases and contributes to basal and claudin-low molecular subclasses of the disease. TNBCs have poor prognosis, display frequent mutations in tumor suppressor gene p53 (TP53), and lack targeted therapies. The MET receptor tyrosine kinase is elevated in TNBC and transgenic Met models (Met(mt)) develop basal-like tumors. To investigate collaborating events in the genesis of TNBC, we generated Met(mt) mice with conditional loss of murine p53 (Trp53) in mammary epithelia. Somatic Trp53 loss, in combination with Met(mt), significantly increased tumor penetrance over Met(mt) or Trp53 loss alone. Unlike Met(mt) tumors, which are histologically diverse and enriched in a basal-like molecular signature, the majority of Met(mt) tumors with Trp53 loss displayed a spindloid pathology with a distinct molecular signature that resembles the human claudin-low subtype of TNBC, including diminished claudins, an epithelial-to-mesenchymal transition signature, and decreased expression of the microRNA-200 family. Moreover, although mammary specific loss of Trp53 promotes tumors with diverse pathologies, those with spindloid pathology and claudin-low signature display genomic Met amplification. In both models, MET activity is required for maintenance of the claudin-low morphological phenotype, in which MET inhibitors restore cell-cell junctions, rescue claudin 1 expression, and abrogate growth and dissemination of cells in vivo. Among human breast cancers, elevated levels of MET and stabilized TP53, indicative of mutation, correlate with highly proliferative TNBCs of poor outcome. This work shows synergy between MET and TP53 loss for claudin-low breast cancer, identifies a restricted claudin-low gene signature, and provides a rationale for anti-MET therapies in TNBC.

PMID: 23509284 [PubMed - in process]

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Met synergizes with p53 loss to induce mammary tumors that possess features of claudin-low breast cancer.

Met synergizes with p53 loss to induce mammary tumors that possess features of claudin-low breast cancer.

Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):E1301-10

PMID: 23509284 [PubMed - in process]

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