5-alpha-reductase: 2013-05-05

2013年5月11日星期六

Development of everolimus, a novel oral mTOR inhibitor, across a spectrum of diseases.

Development of everolimus, a novel oral mTOR inhibitor, across a spectrum of diseases.

Ann N Y Acad Sci. 2013 May 9;

Authors: Lebwohl D, Anak O, Sahmoud T, Klimovsky J, Elmroth I, Haas T, Posluszny J, Saletan S, Berg W

Abstract
Everolimus is a potent, oral inhibitor of the mammalian target of rapamycin (mTOR) that has been investigated in multiple clinical development programs since 1996. A unique collaboration between academic and pharmaceutical experts fostered research that progressed rapidly, with simultaneous indication findings across numerous tumor types. Initially developed for the prophylaxis of organ transplant rejection, everolimus has demonstrated efficacy and safety for the treatment of patients with various types of cancer (renal cell carcinoma, neuroendocrine tumors of pancreatic origin, and breast cancer) and for adult and pediatric patients with tuberous sclerosis complex. The FDA approval of everolimus for these diseases has addressed several unmet medical needs and is widely accepted by the medical community where treatment options may be limited. An extensive clinical development program is ongoing to establish the role of everolimus as monotherapy, or in combination with other agents, in the treatment of a broad spectrum of malignancies.

PMID: 23659703 [PubMed - as supplied by publisher]

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Development of everolimus, a novel oral mTOR inhibitor, across a spectrum of diseases.

Development of everolimus, a novel oral mTOR inhibitor, across a spectrum of diseases.

Ann N Y Acad Sci. 2013 May 9;

Authors: Lebwohl D, Anak O, Sahmoud T, Klimovsky J, Elmroth I, Haas T, Posluszny J, Saletan S, Berg W

PMID: 23659703 [PubMed - as supplied by publisher]

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Efficacy and safety of short-term use of COX-2 inhibitors in patients after an acute stroke with musculoskeletal pain.

Efficacy and safety of short-term use of COX-2 inhibitors in patients after an acute stroke with musculoskeletal pain.

Ann Indian Acad Neurol. 2013 Jan;16(1):47-52

Authors: Rabadi MH, Rabadi FM, Hallford G, Aston CE

Abstract
OBJECTIVE: Musculoskeletal pain commonly occurs in the elderly, many of whom are also prone to suffer from strokes. We studied whether short-term use (? 4 weeks) of cyclooxygenase-2 (COX-2) inhibitors for musculoskeletal pain in stroke patients helped them to participate in their therapies and was safe and efficacious.
MATERIALS AND METHODS: Three hundred and three patients admitted consecutively with first ischemic stroke were studied. Two cohorts were defined, based on whether patients with acute stroke had sufficient musculoskeletal pain that warranted oral COX-2 inhibitors (COX-2 group) or not (case-matched controls). Primary efficacy measures were change in Fugl-Meyer (F-M) pain score and change in total functional independence measure (TFIM) scores on discharge from hospital. Safety was judged by the incidence of vascular episodes during the study period.
RESULTS: From the original 303 patients, 64 patients in the COX-2 group were matched with 64 patients in the non-COX-2 group. The groups were matched for age (�5 years), gender, and admission TFIM score (� 5 points). Baseline characteristics between the 2 groups were similar. The primary and secondary outcome measures were similar between the 2 groups, except for ambulation endurance, which favored the non-COX-2 group (P < 0.03). Greater change in the pain score (less pain) was found in the COX-2 group; this effect was strongest in patients who were independent prior to their stroke (on post hoc analysis). There were too few adverse events in either group of any significance.
CONCLUSIONS: The short-term use of COX-2 inhibitors reduced musculoskeletal pain in acute stroke patients, improved functional motor outcome, and were found to be safe.

PMID: 23661962 [PubMed - in process]

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Efficacy and safety of short-term use of COX-2 inhibitors in patients after an acute stroke with musculoskeletal pain.

Efficacy and safety of short-term use of COX-2 inhibitors in patients after an acute stroke with musculoskeletal pain.

Ann Indian Acad Neurol. 2013 Jan;16(1):47-52

Authors: Rabadi MH, Rabadi FM, Hallford G, Aston CE

PMID: 23661962 [PubMed - in process]

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Incidence and risk of treatment-related mortality in cancer patients treated with the mammalian target of rapamycin inhibitors.

Incidence and risk of treatment-related mortality in cancer patients treated with the mammalian target of rapamycin inhibitors.

Ann Oncol. 2013 May 8;

Authors: Choueiri TK, Je Y, Sonpavde G, Richards CJ, Galsky MD, Nguyen PL, Schutz F, Heng DY, Kaymakcalan MD

Abstract
BACKGROUND: Inhibition of the mammalian target of rapamycin (mTOR) is an established treatment for multiple malignancies. We carried out an up-to-date meta-analysis to determine the risk of fatal adverse events (FAEs) in cancer patients treated with mTOR inhibitors. PATIENTS AND METHODS: PubMed, conferences and clinicaltrials.gov databases were searched for articles reported from January 1966 to June 2012. Eligible studies were limited to approved mTOR inhibitors (everolimus and temsirolimus) and reported on patients with cancer, randomized design and adequate safety profiles. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: In all, 3193 patients from eight randomized, controlled trials (RCTs) were included, 2236 from everolimus trials and 957 from temsirolimus trials. The relative risk (RR) of FAEs related to mTOR inhibitors use was 2.20 (95% CI, 1.25-3.90; P = 0.006) compared with control patients. On subgroup analysis, no difference in the rate of FAEs was found between everolimus and temsirolimus or between tumor types [renal cell carcinoma (RCC) versus non-RCC]. No evidence of publication bias was observed. CONCLUSION: The use of mTOR inhibitors is associated with a small but higher risk of FAEs compared to control patients. In the appropriate clinical scenario, the use of these drugs remains justified in their approved indications.

PMID: 23658373 [PubMed - as supplied by publisher]

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2013年5月10日星期五

Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Transfusion. 2012 Nov;52(11):2406-13

Authors: Avanzi MP, Chen A, He W, Mitchell WB

Abstract
BACKGROUND: Large-scale in vitro production of platelets (PLTs) from cord blood stem cells is one goal of stem cell research. One step toward this goal will be to produce polyploid megakaryocytes capable of releasing high numbers of PLTs. Megakaryocyte polyploidization requires distinct cytoskeletal and cellular mechanisms, including actin polymerization, myosin activation, microtubule formation, and increased DNA production. In this study we variably combined inhibition of these principal mechanisms of cytokinesis with the goal of driving polyploidization in megakaryocytes.
STUDY DESIGN AND METHODS: Megakaryocytes were derived from umbilical cord blood and cultured with reagents that inhibit distinct mechanisms of cytokinesis: Rho-Rock inhibitor (RRI), Src inhibitor (SI), nicotinamide (NIC), aurora B inhibitor (ABI), and myosin light chain kinase inhibitor (MLCKI). Combinations of reagents were used to determine their interactions and to maximize megakaryocyte ploidy.
RESULTS: Treatment with RRI, NIC, SI, and ABI, but not with MLCKI, increased the final ploidy and RRI was the most effective single reagent. RRI and MLCKI, both inhibitors of MLC activation, resulted in opposite ploidy outcomes. Combinations of reagents also increased ploidy and the use of NIC, SI, and ABI was as effective as RRI alone. Addition of MLCKI to NIC, SI, and ABI reached the highest level of polyploidization.
CONCLUSION: Megakaryocyte polyploidization results from modulation of a combination of distinct cytokinesis pathways. Reagents targeting distinct cytoskeletal pathways produced additive effects in final megakaryocyte ploidy. The RRI, however, showed no additive effect but produced a high final ploidy due to overlapping inhibition of multiple cytokinesis pathways.

PMID: 22612069 [PubMed - indexed for MEDLINE]

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Protein tyrosine phosphatase encoded in Cotesia plutellae bracovirus suppresses a larva-to-pupa metamorphosis of the diamondback moth, Plutella xylostella.

Protein tyrosine phosphatase encoded in Cotesia plutellae bracovirus suppresses a larva-to-pupa metamorphosis of the diamondback moth, Plutella xylostella.

Comp Biochem Physiol A Mol Integr Physiol. 2013 May 4;

Authors: Kim J, Hepat R, Lee D, Kim Y

Abstract
Parasitization by an endoparasitoid wasp, Cotesia plutellae, inhibits a larva-to-pupa metamorphosis of the diamondback moth, Plutella xylostella. This study tested an inhibitory effect of C. plutellae bracovirus (CpBV) on the metamorphosis of P. xylostella. Parasitized P. xylostella exhibited significantly reduced prothoracic gland (PTG) development at the last instar compared to nonparasitized larvae. Expression of the ecdysone receptor was markedly suppressed during the last instar larvae parasitized by C. plutellae. By contrast, expression of the insulin receptor significantly increased in the parasitized larvae. Microinjection of CpBV significantly inhibited the larva-to-pupa metamorphosis of nonparasitized larvae in a dose-dependent manner. Injection of CpBV also inhibited the expression of the ecdysone receptor and increased the expression of the insulin receptor. Individual CpBV segments were transiently expressed in its encoded genes in nonparasitized larvae and screened to determine antimetamorphic viral gene(s). Out of 21 CpBV segments, two viral segments (CpBV-S22 and CpBV-S27) were proved to inhibit larva-to-pupa metamorphosis by transient expression assay. RNA interference of each gene encoded in the viral segments was applied to determine antimetamorphic gene(s). Protein tyrosine phosphatase, early expressed gene, and four hypothetical genes were selected to be associated with the antimetamorphic activity of CpBV. These results suggest that antimetamorphosis of P. xylostella parasitized by C. plutellae is induced by inhibiting PTG development and subsequent ecdysteroid signaling with viral factors of CpBV.

PMID: 23651929 [PubMed - as supplied by publisher]

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Role of statins in the development and progression of age-related macular degeneration.

Role of statins in the development and progression of age-related macular degeneration.

Retina. 2013 Feb;33(2):414-22

Authors: VanderBeek BL, Zacks DN, Talwar N, Nan B, Stein JD

Abstract
PURPOSE: To determine if statins are associated with the development or progression of age-related macular degeneration (AMD).
METHODS: A large, national insurance claims database was reviewed to identify individuals aged 60 years or older who were enrolled for ?2 years and had ?1 visits to an eye provider. Prescription claims for statins within a 24-month look-back period and outpatient lipid laboratory values were also reviewed. Cox regression analysis was used to determine whether statin use was associated with the development of nonexudative or exudative AMD or progressing from nonexudative to exudative AMD.
RESULTS: Of the 107,007 beneficiaries eligible for the nonexudative AMD analysis, 4,647 incident cases of nonexudative AMD occurred. Seven hundred and ninety-two incident cases of exudative AMD were found among the 113,111 beneficiaries eligible for the exudative AMD analysis. Of the 10,743 beneficiaries with known nonexudative AMD eligible for the progression model, 404 progressed to exudative AMD during their time in the plan. After multivariable analysis, statin use was not associated with the development of nonexudative AMD (P > 0.05). Statin use of >12 months was associated with an increased hazard for developing exudative AMD (P < 0.005). Among those taking statins, only enrollees with the highest lipid levels had an increased hazard of developing exudative AMD (P < 0.05).
CONCLUSION: In those with elevated lipid levels, >1 year of statin use was associated with an increased hazard for exudative AMD. Lipid status influences the relationship between statins and the risk of AMD. Because of a number of limitations in study design, these observations warrant further study and should not be the rationale for any changes in the use of statins to treat dyslipidemias.

PMID: 23314233 [PubMed - indexed for MEDLINE]

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Inhibition of MET receptor tyrosine kinase and its ligand hepatocyte growth factor.

Inhibition of MET receptor tyrosine kinase and its ligand hepatocyte growth factor.

J Thorac Oncol. 2012 Dec;7(16 Suppl 5):S372-4

Authors: Sadiq AA, Salgia R

PMID: 23160322 [PubMed - indexed for MEDLINE]

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KRC-327, a selective novel inhibitor of c-Met receptor tyrosine kinase with anticancer activity.

KRC-327, a selective novel inhibitor of c-Met receptor tyrosine kinase with anticancer activity.

Cancer Lett. 2013 May 1;331(2):158-66

Authors: Park BH, Jung KH, Yun SM, Hong SW, Ryu JW, Jung H, Ha JD, Lee J, Hong SS

Abstract
c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been reported to be involved in tumorigenesis and metastatic progression. We synthesized a novel triazolopyridazine derivative KRC-327 which selectively targets the c-Met. When we performed receptor tyrosine kinases (RTKs) array with 42 different phosphorylated-RTKs, KRC-327 strongly inhibited expression of activated c-Met in MKN-45 cancer cells. This was confirmed by immunofluorescence staining. Also, KRC-327 decreased the expression of Gab1, Akt, signal transducer and activator of transcription 3 (STAT3) and Erk, down-stream signals of c-Met. KRC-327 strongly suppressed the growth of c-Met over-expressed cancer cells (MKN-45, SNU-638, SNU-5), while not in c-Met absent cancer cell lines (MKN-1, SNU-1). Furthermore, KRC-327 effectively induced cell cycle arrest, especially G0/G1 arrest by increasing expression of p21, p27 and decreasing that of cyclin D1. In the ligand-induced functional studies, KRC-327 inhibited proliferation of HGF-stimulated BxPC-3 cells, the migration of HGF-stimulated AGS cancer cells, and suppressed colony formation in HGF-stimulated U-87MG cells. In xenograft animal models, KRC-327 significantly not only delayed tumor growth but also suppressed phosphorylation of c-Met and its signaling cascades as well as proliferation. Taken together, these results demonstrate that KRC-327 selectively targets c-Met, resulting in inhibition of cell growth and proliferation. Therefore, we suggest that KRC-327 may be a novel drug candidate with the therapeutic potential of targeting c-Met in human cancer.

PMID: 23340177 [PubMed - indexed for MEDLINE]

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2013年5月9日星期四

The progression free survival-plateau with vascular endothelial growth factor receptor inhibitors - Is there more to come?

The progression free survival-plateau with vascular endothelial growth factor receptor inhibitors - Is there more to come?

Eur J Cancer. 2013 Apr 16;

Authors: Gr�nwald V, Merseburger AS

Abstract
The field of renal cell carcinoma (RCC) treatment has changed dramatically during recent years. Sunitinib, sorafenib and pazopanib were the first generation of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) to have significant clinical activity in metastatic clear cell RCC. These TKI share inhibition of VEGFR family members, but differ in their ability to block other cellular kinases. Axitinib and tivozanib are 2nd generation TKIs, which show high specificity for VEGFR inhibition and exert a favourable toxicity profile. Both agents have succeeded in pivotal clinical trials, which were the first studies to compare two distinct TKIs. Progression free survival (PFS) shows an advantage for the 2nd generation TKIs, but also curbs enthusiasm for limitless PFS expectations with a PFS plateau of 13-14months in 1st line treatment. More recently, novel targets have gained attention in RCC, such as the mesenchymal epithelial transition factor also known as the MET receptor and the fibroblast growth factor receptor (FGFR). These receptors are included into the inhibitory profiles of third generation TKIs such as cabozantinib or dovitinib, which showed promising activity in early clinical trials. Randomised controlled trials explore the role of these agents, and whether the expansion of targets inhibited may lead to more effective treatments in RCC.

PMID: 23601669 [PubMed - as supplied by publisher]

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Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors.

Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors.

Bioorg Med Chem. 2013 Apr 16;

Authors: Li S, Zhao Y, Wang K, Gao Y, Han J, Cui B, Gong P

Abstract
A series of novel 4-(2-fluorophenoxy)quinoline derivatives containing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG and SMMC-7721). All the prepared compounds showed moderate to excellent antiproliferative activity, and the analysis of their structure-activity relationships indicated that 2-chloro or 2-trifluoromethyl substituted phenyl group on the 1-position of cinnoline ring was more favorable for antitumor activity. In this study, a promising compound 33, with a c-Met IC50 value of 0.59nM, was identified as a multitargeted receptor tyrosine kinase inhibitor.

PMID: 23628470 [PubMed - as supplied by publisher]

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Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors.

Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors.

Bioorg Med Chem. 2013 Apr 16;

Authors: Li S, Zhao Y, Wang K, Gao Y, Han J, Cui B, Gong P

PMID: 23628470 [PubMed - as supplied by publisher]

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mTOR, p70S6K, AKT and ERK1/2 levels predict sensitivity to mTOR and PI3K/mTOR inhibitors in human bronchial carcinoids.

mTOR, p70S6K, AKT and ERK1/2 levels predict sensitivity to mTOR and PI3K/mTOR inhibitors in human bronchial carcinoids.

Endocr Relat Cancer. 2013 May 7;

Authors: Gagliano T, Bellio M, Gentilin E, Mol� D, Tagliati F, Schiavon M, Cavallesco NG, Andriolo LG, Rea F, Degli Uberti EC, Zatelli MC

Abstract
Bronchial carcinoids (BC) are rare neuroendocrine tumors that are still orphan of medical treatment. Human BC primary cultures may display resistance to Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), in terms of cell viability reduction. Our aim is to assess whether the novel dual PI3K/mTOR inhibitor, NVP-BEZ235, may be effective in Everolimus-resistant human BC tissues and cell lines. In addition, we search for possible markers of mTOR inhibitors efficacy, that may help in identifying the patients that may benefit from mTOR inhibitors treatment, sparing them from ineffective therapy. We found that NVP-BEZ235 is twice as potent as Everolimus in reducing cell viability and activating apoptosis in human BC tissues that display sensitivity to mTOR inhibitors, but is not effective in Everolimus-resistant BC tissues and cell lines, that by-pass cyclin D1 down-regulation and escape G0/G1 blockade. Rebound AKT activation was not observed in response to treatment with either mTOR inhibitor in 'resistant' BC cells. In addition to total mTOR levels, putative markers of BC sensitivity to mTOR inhibitors are represented by AKT, p70S6K and ERK1/2 protein levels. Finally, we validated these markers in an independent BC group. These data indicate that the dual PI3K/mTOR inhibitor NVP-BEZ235 is more potent than Everolimus in reducing human BC cell proliferation. 'Resistant' cells display lower levels of mTOR, p70S6K, AKT and ERK1/2, indicating that these proteins may be useful as predictive markers of resistance to mTOR and PI3K/mTOR inhibitors in human BC.

PMID: 23653462 [PubMed - as supplied by publisher]

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2013年5月8日星期三

Oral ulcers in patients with advanced breast cancer receiving everolimus: a case series report on clinical presentation and management.

Oral ulcers in patients with advanced breast cancer receiving everolimus: a case series report on clinical presentation and management.

Oral Surg Oral Med Oral Pathol Oral Radiol. 2013 May 3;

Authors: Nicolatou-Galitis O, Nikolaidi A, Athanassiadis I, Papadopoulou E, Sonis S

Abstract
OBJECTIVE: We report the clinical features and management outcomes in 7 patients with everolimus-related stomatitis. STUDY DESIGN: Fifteen women with hormone-receptor-positive advanced breast cancer receiving everolimus combined with exemestane were prospectively evaluated to assess the development of stomatitis. Oral ulcers were diagnosed based on established criteria. RESULTS: Seven patients developed stomatitis (46.6%). All patients were treated with topical dexamethasone solution, while everolimus was temporarily discontinued in 4 patients. Stomatitis resolved within 1-2 weeks. Two of the 4 patients, who had interrupted everolimus, developed recurrent stomatitis following drug resume and everolimus was again discontinued and restarted after 2 weeks. To date, 5 patients receive everolimus in full dose. The 2 patients, who developed recurrent stomatitis, received a reduced dose. CONCLUSIONS: Everolimus-related oral ulcers were frequent and led to dose modifications. Controlled trials, endorsing a consensus in terminology, are needed to evaluate measures on prevention and management of this unique toxicity.

PMID: 23643584 [PubMed - as supplied by publisher]

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The progression free survival-plateau with vascular endothelial growth factor receptor inhibitors - Is there more to come?

The progression free survival-plateau with vascular endothelial growth factor receptor inhibitors - Is there more to come?

Eur J Cancer. 2013 Apr 16;

Authors: Gr�nwald V, Merseburger AS

PMID: 23601669 [PubMed - as supplied by publisher]

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The progression free survival-plateau with vascular endothelial growth factor receptor inhibitors - Is there more to come?

The progression free survival-plateau with vascular endothelial growth factor receptor inhibitors - Is there more to come?

Eur J Cancer. 2013 Apr 16;

Authors: Gr�nwald V, Merseburger AS

PMID: 23601669 [PubMed - as supplied by publisher]

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Transcriptional and Non-Transcriptional Functions of PPAR?/? in Non-Small Cell Lung Cancer.

Transcriptional and Non-Transcriptional Functions of PPAR?/? in Non-Small Cell Lung Cancer.

PLoS One. 2012;7(9):e46009

Authors: Genini D, Garcia-Escudero R, Carbone GM, Catapano CV

Abstract
Peroxisome proliferator-activated receptor ?/? (PPAR?/?) is a nuclear receptor involved in regulation of lipid and glucose metabolism, wound healing and inflammation. PPAR?/? has been associated also with cancer. Here we investigated the expression of PPAR?/? and components of the prostaglandin biosynthetic pathway in non-small cell lung cancer (NSCLC). We found increased expression of PPAR?/?, Cox-2, cPLA(2), PGES and VEGF in human NSCLC compared to normal lung. In NSCLC cell lines PPAR?/? activation increased proliferation and survival, while PPAR?/? knock-down reduced viability and increased apoptosis. PPAR?/? agonists induced Cox-2 and VEGF transcription, suggesting the existence of feed-forward loops promoting cell survival, inflammation and angiogenesis. These effects were seen only in high PPAR?/? expressing cells, while low expressing cells were less or not affected. The effects were also abolished by PPAR?/? knock-down or incubation with a PPAR?/? antagonist. Induction of VEGF was due to both binding of PPAR?/? to the VEGF promoter and PI3K activation through a non-genomic mechanism. We found that PPAR?/? interacted with the PI3K regulatory subunit p85? leading to PI3K activation and Akt phosphorylation. Collectively, these data indicate that PPAR?/? might be a central element in lung carcinogenesis controlling multiple pathways and representing a potential target for NSCLC treatment.

PMID: 23049921 [PubMed - indexed for MEDLINE]

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2013年5月7日星期二

AML1-ETO mediates hematopoietic self-renewal and leukemogenesis through a COX/?-catenin signaling pathway.

AML1-ETO mediates hematopoietic self-renewal and leukemogenesis through a COX/?-catenin signaling pathway.

Blood. 2013 May 3;

Authors: Zhang Y, Wang J, Wheat J, Chen X, Jin S, Sadrzadeh H, Fathi AT, Peterson RT, Kung AL, Sweetser DA, Yeh JR

Abstract
Developing novel therapies that suppress self-renewal of leukemia stem cells (LSCs) may reduce the likelihood of relapses and extend long-term survival of patients with acute myelogenous leukemia (AML). AML1-ETO (AE) is an oncogene that plays an important role in inducing self-renewal of hematopoietic stem/progenitor cells (HSPCs), leading to the development of LSCs. Previously, using a zebrafish model of AE and a whole-organism chemical suppressor screen, we have discovered that AE induces specific hematopoietic phenotypes in embryonic zebrafish through a cyclooxygenase-2 (COX-2) and ?-catenin-dependent pathway. Here, we show that AE also induces expression of the Cox2 gene and activates ?-catenin in mouse bone marrow cells. Inhibition of COX suppresses ?-catenin activation and serial replating of AE(+) mouse HSPCs. Genetic knockdown of ?-catenin also abrogates the clonogenic growth of AE(+) mouse HSPCs and human leukemia cells. In addition, treatment with nimesulide, a COX-2 selective inhibitor, dramatically suppresses xenograft tumor formation and inhibits in vivo progression of human leukemia cells. In summary, our data indicate an important role of a COX/?-catenin-dependent signaling pathway in tumor initiation, growth and self-renewal, and provide the rationale for testing potential benefits from common COX inhibitors as a part of AML treatments.

PMID: 23645839 [PubMed - as supplied by publisher]

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Strategies to address drug interaction potential for antibody-drug conjugates in clinical development.

Strategies to address drug interaction potential for antibody-drug conjugates in clinical development.

Bioanalysis. 2013 May;5(9):1115-30

Authors: Lu D, Sahasranaman S, Zhang Y, Girish S

Abstract
Antibody-drug conjugates (ADCs) are a unique class of therapeutic proteins with both small and large molecular components. In vivo, ADCs are processed to multiple clinically relevant analytes, each with distinct PK properties. This increases the complexity for ADC drug interaction (DI) assessment. Furthermore, given the usually narrow therapeutic range for ADCs, a thorough risk assessment is essential to establish benefit/risk for patients. Therefore, an early understanding of the ADC catabolism and elimination pathways and cytochrome P450 reaction phenotyping, cytochrome P450 inhibition and induction potential, transporter interaction and inhibition potential for the cytotoxic drug catabolites assessed by in vitro and preclinical studies is essential. This information would be integrated with the clinical PK and PD properties of the ADC-related analytes for a theoretical risk assessment of ADC DI in combination therapy. ADC DI assessment in clinical studies will further support the theoretical risk assessment and the conclusions for the labeling statement.

PMID: 23641700 [PubMed - in process]

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Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Transfusion. 2012 Nov;52(11):2406-13

Authors: Avanzi MP, Chen A, He W, Mitchell WB

PMID: 22612069 [PubMed - indexed for MEDLINE]

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Commentary on: Everolimus for Angiomyolipoma Associated With Tuberous Sclerosis Complex or Sporadic Lymphangioleiomyomatosis (EXIST-2): A Multicentre, Randomised, Double-blind, Placebo-controlled Trial.

Commentary on: Everolimus for Angiomyolipoma Associated With Tuberous Sclerosis Complex or Sporadic Lymphangioleiomyomatosis (EXIST-2): A Multicentre, Randomised, Double-blind, Placebo-controlled Trial.

Urology. 2013 May 2;

Authors: Black P

PMID: 23642941 [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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2013年5月6日星期一

The human Lgl polarity gene, Hugl-2, induces MET and suppresses Snail tumorigenesis.

The human Lgl polarity gene, Hugl-2, induces MET and suppresses Snail tumorigenesis.

Oncogene. 2013 Mar 14;32(11):1396-407

Authors: Kashyap A, Zimmerman T, Erg�l N, Bosserhoff A, Hartman U, Alla V, Bataille F, Galle PR, Strand S, Strand D

Abstract
Lethal giant larvae proteins have key roles in regulating polarity in a variety of cell types and function as tumour suppressors. A transcriptional programme initiated by aberrant Snail expression transforms epithelial cells to potentially aggressive cancer cells. Although progress in defining the molecular determinants of this programme has been made, we have little knowledge as to how the Snail-induced phenotype can be suppressed. In our studies we identified the human lethal giant larvae homologue 2, Hugl-2, (Llgl2/Lgl2) polarity gene as downregulated by Snail. Snail binds E-boxes in the Hugl-2 promoter and represses Hugl-2 expression, whereas removal of the E-boxes releases Hugl-2 from Snail repression. We demonstrate that inducing Hugl-2 in cells with constitutive Snail expression reverses the phenotype including changes in morphology, motility, tumour growth and dissemination in vivo, and expression of epithelial markers. Hugl-2 expression reduced the nuclear localization of Snail and thus binding of Snail to its target promoters. Our results placing Hugl-2 within the Snail network as well as its ability to suppress Snail carcinogenesis identifies Hugl-2 as a target molecule driving cascades, which may have preventative and therapeutic promise to minimize cancer progression.

PMID: 22580609 [PubMed - indexed for MEDLINE]

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Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi-targeted kinase inhibitors in pimasertib-resistant human lung and colorectal cancer cells.

Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi-targeted kinase inhibitors in pimasertib-resistant human lung and colorectal cancer cells.

Int J Cancer. 2013 Apr 30;

Authors: Martinelli E, Troiani T, D'Aiuto E, Morgillo F, Vitagliano D, Capasso A, Costantino S, Ciuffreda LP, Merolla F, Vecchione L, De Vriendt V, Tejpar S, Nappi A, Sforza V, Martini G, Berrino L, De Palma R, Ciardiello F

Abstract
The RAS/RAF/MEK/MAPK and the PTEN/PI3K/AKT/mTOR pathways are key regulators of proliferation and survival in human cancer cells. Selective inhibitors of different transducer molecules in these pathways have been developed as molecular targeted anti-cancer therapies. The in vitro and in vivo anti-tumor activity of pimasertib, a selective MEK 1/2 inhibitor, alone or in combination with a PI3K inhibitor (PI3Ki), a mTOR inhibitor (everolimus), or with multi-targeted kinase inhibitors (sorafenib and regorafenib), that block also BRAF and CRAF, were tested in a panel of eight human lung and colon cancer cell lines. Following pimasertib treatment, cancer cell lines were classified as pimasertib-sensitive (IC50 for cell growth inhibition of 0.001�M) or pimasertib-resistant. Evaluation of basal gene expression profiles by microarrays identified several genes that were up-regulated in pimasertib-resistant cancer cells and that were involved in both RAS/RAF/MEK/MAPK and PTEN/PI3K/AKT/mTOR pathways. Therefore, a series of combination experiments with pimasertib and either PI3Ki, everolimus, sorafenib or regorafenib were conducted, demonstrating a synergistic effect in cell growth inhibition and induction of apoptosis with sustained blockade in MAPK- and AKT-dependent signaling pathways in pimasertib-resistant human colon carcinoma (HCT15) and lung adenocarcinoma (H1975) cells. Finally, in nude mice bearing established HCT15 and H1975 subcutaneous tumor xenografts, the combined treatment with pimasertib and BEZ235 (a dual PI3K/mTOR inhibitor) or with sorafenib caused significant tumor growth delays and increase in mice survival as compared to single agent treatment. These results suggest that dual blockade of MAPK and PI3K pathways could overcome intrinsic resistance to MEK inhibition. � 2013 Wiley Periodicals, Inc.

PMID: 23629727 [PubMed - as supplied by publisher]

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The progression free survival-plateau with vascular endothelial growth factor receptor inhibitors - Is there more to come?

The progression free survival-plateau with vascular endothelial growth factor receptor inhibitors - Is there more to come?

Eur J Cancer. 2013 Apr 16;

Authors: Gr�nwald V, Merseburger AS

PMID: 23601669 [PubMed - as supplied by publisher]

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Ataxia telangiectasia mutated (ATM) is dispensable for endonuclease I-SceI-induced homologous recombination in mouse embryonic stem cells.

Ataxia telangiectasia mutated (ATM) is dispensable for endonuclease I-SceI-induced homologous recombination in mouse embryonic stem cells.

J Biol Chem. 2013 Mar 8;288(10):7086-95

Authors: Rass E, Chandramouly G, Zha S, Alt FW, Xie A

Abstract
Ataxia telangiectasia mutated (ATM) is activated upon DNA double strand breaks (DSBs) and phosphorylates numerous DSB response proteins, including histone H2AX on serine 139 (Ser-139) to form ?-H2AX. Through interaction with MDC1, ?-H2AX promotes DSB repair by homologous recombination (HR). H2AX Ser-139 can also be phosphorylated by DNA-dependent protein kinase catalytic subunit and ataxia telangiectasia- and Rad3-related kinase. Thus, we tested whether ATM functions in HR, particularly that controlled by ?-H2AX, by comparing HR occurring at the euchromatic ROSA26 locus between mouse embryonic stem cells lacking either ATM, H2AX, or both. We show here that loss of ATM does not impair HR, including H2AX-dependent HR, but confers sensitivity to inhibition of poly(ADP-ribose) polymerases. Loss of ATM or H2AX has independent contributions to cellular sensitivity to ionizing radiation. The ATM-independent HR function of H2AX requires both Ser-139 phosphorylation and ?-H2AX/MDC1 interaction. Our data suggest that ATM is dispensable for HR, including that controlled by H2AX, in the context of euchromatin, excluding the implication of such an HR function in genomic instability, hypersensitivity to DNA damage, and poly(ADP-ribose) polymerase inhibition associated with ATM deficiency.

PMID: 23355489 [PubMed - indexed for MEDLINE]

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2013年5月5日星期日

The human Lgl polarity gene, Hugl-2, induces MET and suppresses Snail tumorigenesis.

The human Lgl polarity gene, Hugl-2, induces MET and suppresses Snail tumorigenesis.

Oncogene. 2013 Mar 14;32(11):1396-407

Authors: Kashyap A, Zimmerman T, Erg�l N, Bosserhoff A, Hartman U, Alla V, Bataille F, Galle PR, Strand S, Strand D

PMID: 22580609 [PubMed - indexed for MEDLINE]

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Biomedicine. Rare cancer successes spawn 'exceptional' research efforts.

Biomedicine. Rare cancer successes spawn 'exceptional' research efforts.

Science. 2013 Apr 19;340(6130):263

Authors: Kaiser J

PMID: 23599454 [PubMed - indexed for MEDLINE]

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Biomedicine. Rare cancer successes spawn 'exceptional' research efforts.

Biomedicine. Rare cancer successes spawn 'exceptional' research efforts.

Science. 2013 Apr 19;340(6130):263

Authors: Kaiser J

PMID: 23599454 [PubMed - indexed for MEDLINE]

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Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Transfusion. 2012 Nov;52(11):2406-13

Authors: Avanzi MP, Chen A, He W, Mitchell WB

PMID: 22612069 [PubMed - indexed for MEDLINE]

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KRC-408, a novel c-Met inhibitor, suppresses cell proliferation and angiogenesis of gastric cancer.

KRC-408, a novel c-Met inhibitor, suppresses cell proliferation and angiogenesis of gastric cancer.

Cancer Lett. 2013 May 10;332(1):74-82

Authors: Hong SW, Jung KH, Park BH, Zheng HM, Lee HS, Choi MJ, Yun JI, Kang NS, Lee J, Hong SS

Abstract
Among many cancer therapeutic targets, c-Met receptor tyrosine kinase has recently given particular attention. This kinase and its ligand, hepatocyte growth factor (HGF), play a central role in cell proliferation and the survival of several human cancers. Thus, we developed KRC-408 as a novel c-Met inhibitor and investigated its anti-cancer effects on human gastric cancer. KRC-408 inhibited the phosphorylation of c-Met and its constitutive downstream effectors such as phosphatidylinositol 3-kinase (PI3K), Akt, Mek, and Erk. This compound was found to exert anti-cancer effects stronger than those of 5-fluorouracil (5-FU) on gastric cancer cells, especially cell lines that overexpressed c-Met. Interestingly, cytotoxicity of KRC-408 was lower than that of 5-FU in normal gastric cells. Apoptosis induced by KRC-408 was accompanied by increased levels of cleaved caspase-3 and PARP as well as DNA condensation and fragmentation. Flow cytometry analysis showed an accumulation of gastric cancer cells in the G2/M phase with concomitant loss of cells in the S phase following treatment with this drug. In the angiogenesis studies, KRC-408 inhibited tube formation and migration of human umbilical vein endothelial cells (HUVECs), and suppressed microvessel sprouting from rat aortic rings ex vivo along with blood vessel formation in a Matrigel plug assay in mice. Results of an in vivo mouse xenograft experiment showed that the administration of KRC-408 significantly delayed tumor growth in a dose-dependent manner, and suppressed Akt and Erk phosphorylation as well CD34 expression in tumor tissues. These findings indicate that KCR-408 may exert anti-tumor effects by directly affecting tumor cell growth or survival via the c-Met receptor tyrosine kinase pathway. We therefore suggest that KRC-408 is a novel therapeutic candidate effective against gastric cancers that overexpress c-Met.

PMID: 23348694 [PubMed - indexed for MEDLINE]

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