5-alpha-reductase: 2012-12-30

2013年1月5日星期六

Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.

Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.

Bioorg Med Chem Lett. 2012 Sep 15;22(18):5903-8

Authors: Raheem IT, Breslin MJ, Fandozzi C, Fuerst J, Hill N, Huszar S, Kandebo M, Kim SH, Ma B, McGaughey G, Renger JJ, Schreier JD, Sharma S, Smith S, Uslaner J, Yan Y, Coleman PJ, Cox CD

Abstract
We describe the discovery of potent and orally bioavailable tetrahydropyridopyrimidine inhibitors of phosphodiesterase 10A by systematic optimization of a novel HTS lead. Lead compound THPP-1 exhibits nanomolar potencies, excellent pharmacokinetic properties, and a clean off-target profile. It displays in vivo target engagement as measured by increased rat striatal cGMP levels upon oral dosing. It shows dose-dependent efficacy in a key pharmacodynamic assay predictive of antipsychotic activity, the psychostimulant-induced rat hyperlocomotion assay. Further, THPP-1 displays significantly fewer preclinical adverse events in assays measuring prolactin secretion, catalepsy, and weight gain, in contrast to the typical and atypical antipsychotics haloperidol and olanzapine.

PMID: 22892116 [PubMed - indexed for MEDLINE]

ecdysone chir-258 dovitinib

A critical role for p130Cas in the progression of pulmonary hypertension in humans and rodents.

A critical role for p130Cas in the progression of pulmonary hypertension in humans and rodents.

Am J Respir Crit Care Med. 2012 Oct 1;186(7):666-76

Authors: Tu L, De Man FS, Girerd B, Huertas A, Chaumais MC, Lecerf F, Fran�ois C, Perros F, Dorfm�ller P, Fadel E, Montani D, Eddahibi S, Humbert M, Guignabert C

Abstract
RATIONALE: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by pulmonary arterial muscularization due to excessive pulmonary vascular cell proliferation and migration, a phenotype dependent upon growth factors and activation of receptor tyrosine kinases (RTKs). p130(Cas) is an adaptor protein involved in several cellular signaling pathways that control cell migration, proliferation, and survival.
OBJECTIVES: We hypothesized that in experimental and human PAH p130(Cas) signaling is overactivated, thereby facilitating the intracellular transmission of signal induced by fibroblast growth factor (FGF)2, epidermal growth factor (EGF), and platelet-derived growth factor (PDGF).
MEASUREMENTS AND MAIN RESULTS: In patients with PAH, levels of p130(Cas) protein and/or activity are higher in the serum, in the walls of distal pulmonary arteries, in cultured smooth muscle cells (PA-SMCs), and in pulmonary endothelial cells (P-ECs) than in control subjects. These abnormalities in the p130(Cas) signaling were also found in the chronically hypoxic mice and monocrotaline-injected rats as models of human PAH. We obtained evidence for the convergence and amplification of the growth-stimulating effect of the EGF-, FGF2-, and PDGF-signaling pathways via the p130(Cas) signaling pathway. We found that daily treatment with the EGF-R inhibitor gefitinib, the FGF-R inhibitor dovitinib, and the PDGF-R inhibitor imatinib started 2 weeks after a subcutaneous monocrotaline injection substantially attenuated the abnormal increase in p130(Cas) and ERK1/2 activation and regressed established pulmonary hypertension.
CONCLUSIONS: Our findings demonstrate that p130(Cas) signaling plays a critical role in experimental and idiopathic PAH by modulating pulmonary vascular cell migration and proliferation and by acting as an amplifier of RTK downstream signals.

PMID: 22798315 [PubMed - indexed for MEDLINE]

zm-447439 rad001 ecdysone

Prognostic value of acquired resistance-related molecules in Japanese patients with NSCLC treated with an EGFR-TKI.

Prognostic value of acquired resistance-related molecules in Japanese patients with NSCLC treated with an EGFR-TKI.

Anticancer Res. 2012 Sep;32(9):3785-90

Authors: Uramoto H, Yamada T, Yano S, Kondo N, Hasegawa S, Tanaka F

Abstract
BACKGROUND: Most patients with lung cancer experience relapse, although epidermal growth factor receptor (EGFR) of tyrosine kinase inhibitor (TKI) has an astounding effect on tumors with EGFR-activating mutations. It is therefore critical to determine the mechanisms of resistance against agents and the prognostic value of acquired resistance-related molecules to EGFR-TKI.
MATERIALS AND METHODS: Tumor specimens were obtained from 19 matched specimens before and after treatment with gefitinib. A retrospective multi-institutional study analyzed the correlation between patients' survival and acquired resistance-related molecules in non-small cell lung cancer (NSCLC) samples, that possessed sensitive EGFR mutations (7 cases: exon 19 deletion, and 12 cases: exon 21 point mutation). The status of the epidermal growth factor receptor (EGFR) and KRAS genes were investigated by polymerase chain reaction (PCR)-based analyses. Real-time PCR assays were also used to evaluate MET gene amplification. The expression of hepatocyte growth factor (HGF) and changes in the epithelial-mesenchymal transition (EMT) status including the expression of E-cadherin and ?-catenin as epithelial markers, and those of vimentin and fibronectin as mesenchymal markers, were evaluated by immunohistochemistry.
RESULTS: Eight of the gefitinib refractory tumors exhibited a secondary threonine-to-methionine mutation at codon 790 in EGFR (T790M). All of the tumors had wild type KRAS gene expression. No MET amplification was detected in any of the samples. A strong expression of HGF was detected in eight of the specimens at post-treatment. A change in the EMT status between pre-and post-treatment was found in five cases. The 5-year survival rate of patients with and without T790M was 86.7% and 13.3%, respectively (p=0.020). The 5-year overall survival (OS) rate for patients with overexpresion and for those with weak expression of HGF was 75.0% and 22.2%, respectively (p=0.259). In addition, the 5-year OS rate for patients with unchanged and changed EMT status was 83.3% and 40.0%, respectively (p=0.123).
CONCLUSION: The current results showed that the presence of T790M is associated with favorable survival. On the other hand, the patients with weak HGF expression and EMT change tend to have a poor survival. The current patients' selection might be changed by discrimination of acquired resistance-related molecules in patients with NSCLC treated with an EGFR-TKI.

PMID: 22993320 [PubMed - indexed for MEDLINE]

ecdysone chir-258 dovitinib

Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.

Discovery of tetrahydropyridopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.

Bioorg Med Chem Lett. 2012 Sep 15;22(18):5903-8

Authors: Raheem IT, Breslin MJ, Fandozzi C, Fuerst J, Hill N, Huszar S, Kandebo M, Kim SH, Ma B, McGaughey G, Renger JJ, Schreier JD, Sharma S, Smith S, Uslaner J, Yan Y, Coleman PJ, Cox CD

PMID: 22892116 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

Cardiovascular adverse effects of anti-inflammatory drugs.

Cardiovascular adverse effects of anti-inflammatory drugs.

Antiinflamm Antiallergy Agents Med Chem. 2012 Dec 31;

Authors: Roubille C, Martel-Pelletier J, Davy JM, Haraoui B, Pelletier JP

Abstract
Anti-inflammatory drugs consist of non-steroidal anti-inflammatory drugs (NSAIDs) including non-selective nsNSAIDs, aspirin, and cyclooxygenase-2 (COX-2)-selective inhibitors also referred to as coxibs, and glucocorticoids (GCs). They are worldwide prescribed drugs for many musculoskeletal conditions, such as osteoarthritis and inflammatory rheumatic diseases. Anti-inflammatory drugs can exert deleterious effects on the cardiovascular system, excluding aspirin. NSAIDs, especially coxibs, have been demonstrated to increase cardiovascular risk and have generated many concerns leading to the reassessment of their benefit/risk ratio. GCs may also induce cardiovascular events, but evidence seems to be less clear. Before prescribing these drugs, an assessment of cardiovascular risk may be judicious.In this review, anti-inflammatory drugs, coxibs, nsNSAIDs and GCs, and the risk of cardiovascular events will be discussed.

PMID: 23286294 [PubMed - as supplied by publisher]

ecdysone chir-258 dovitinib

2013年1月4日星期五

The combination of IKK? inhibitor and everolimus modulates expression of IL-10 in HTLV-1-infected T cells.

The combination of IKK? inhibitor and everolimus modulates expression of IL-10 in HTLV-1-infected T cells.

Immunology. 2012 Dec 27;

Authors: Nishioka C, Ikezoe T, Yang J, Udaka K, Yokoyama A

Abstract
Adult T-cell leukemia-lymphoma (ATLL) is an aggressive malignancy of CD4(+) /CD25(+) T lymphocytes, and characterized with severely compromised immunosystem in which the human T-cell lymphotropic virus type 1 (HTLV-1) has been recognized as the etiologic agent. This study found that an I?B kinase ? (IKK?) inhibitor Bay11-7082 inactivated mammalian target of rapamycin (mTOR), signal transducer and activator of transcription 3 (STAT3), and transcription factor nuclear factor-?B (NF-?B) in HTLV-1-infected T cells, which was significantly enhanced in the presence of an mTOR inhibitor everolimus. In addition, Bay11-7082 decreased production of immunosuppressive cytokine interleukin-10 (IL-10), which was further downregulated when Bay11-7082 was combined with evelolimus in HTLV-I-infected T and ATLL cells isolated from patients. IL-10 is known to inhibit maturation and the antigen-presenting function of dendritic cells (DCs). The culture media of HTLV-I-infected MT-1 cells which contained a great amout of IL-10 hampered TNF-?-induced maturation of DCs isolated from healthy volunteers. Notably, culture supernatant of MT-1 cells treated by the combination of Bay11-7082 and everolimus augmented maturation of DCs in association with a decrease in production of IL-10 and enhanced the allostimulatory function of DCs. Similarly, when DCs isolated from ATLL patients were treated with the combination of Bay11-7082 and everolimus, they were fully maturated and their capability to stimulate proliferation of lymphocytes was augmented. Taken together, the combination of Bay11-7082 and everolimus might exhibit immunostimulatory properties in HTLV-1-infected T and ATLL cells isolated from patients, and this combination may be potentially therapeutic to regain the compromised immunosystem in ATLL patients. � 2012 The Authors. Immunology � 2012 Blackwell Publishing Ltd.

PMID: 23278479 [PubMed - as supplied by publisher]

dna-pk coxinhibitors c-met inhibitors

Tetraploidization increases sensitivity to Aurora B kinase inhibition.

Tetraploidization increases sensitivity to Aurora B kinase inhibition.

Cell Cycle. 2012 Jul 1;11(13):2567-77

Authors: Marxer M, Foucar CE, Man WY, Chen Y, Ma HT, Poon RY

Abstract
Aurora kinases are overexpressed in many cancers and are targets for anticancer drugs. The yeast homolog of Aurora B kinase, IPL1, was found to be a ploidy-specific lethality gene. Given that polyploidization is a common feature of many cancers, we hypothesized polyploidization also sensitizes mammalian cells to inhibition of Aurora kinases. Using two models of apparent diploid vs. tetraploid cell lines (one based on the hepatocellular carcinoma cell line Hep3B and another on untransformed mouse fibroblasts), we found that tetraploid cells were more sensitive to Aurora B inhibition than their diploid counterparts. Apoptosis could be induced in tetraploid cells by two different Aurora B inhibitors. Furthermore, tetraploid cells were sensitive to Aurora B inhibition but were not affected by Aurora A inhibition. Interestingly, the underlying mechanism was due to mitotic slippage and the subsequent excessive genome reduplication. In support of this, abolition of cytokinesis with dihydrocytochalasin B resulted in similar effects on tetraploid cells as Aurora B inhibition. These results indicate that inhibition of Aurora B or cytokinesis can promote apoptosis effectively in polyploid cancer cells.

PMID: 22722494 [PubMed - in process]

chir-258 dovitinib dna-pk

Biological significance and targeting of c-Met tyrosine kinase receptor in cancer�.

Biological significance and targeting of c-Met tyrosine kinase receptor in cancer�.

Front Biosci. 2013;18:454-73

Authors: Goetsch L, Caussanel V, Corvaia N

Abstract
c-Met is a tyrosine kinase receptor largely described to be involved in cancer progression and metastasis. In such pathologic situation, many alterations of this receptor were noticed that include transcriptional overexpression, gene amplification, somatic or germline mutations and/or ligand dependent autocrine/paracrine loops. More recently it has also been suggested that c-Met would be involved in resistance to targeted therapies directed towards EGFR or angiogenesis. Major efforts from a large number of pharmaceutical companies are invested dedicated to evaluate the efficacy of either small molecule inhibitors or monoclonal antibodies directed against c-Met or its unique ligand HGF. A series of promising results from the first completed clinical trials indicated that compounds targeting c-Met have an acceptable toxicity profile and that efficacy was noticed in some treated patients. Non squamous NSCLC patients that express more often high levels of c-Met seemed to represent a most sensitive subset for and anti-c-Met/erlotinib therapy. Many Phase III trials are currently recruiting and a particular effort was performed in order to discover biomarkers associated with efficacy and patient selection. This review will provide an overview of the current knowledge on the c-Met axis for development of novel therapeutics in Oncology.

PMID: 23276936 [PubMed - in process]

coxinhibitors c-met inhibitors zm-447439

Phenol oxidase is a necessary enzyme for the silkworm molting which is regulated by molting hormone.

Phenol oxidase is a necessary enzyme for the silkworm molting which is regulated by molting hormone.

Mol Biol Rep. 2012 Dec 29;

Authors: Wang MX, Lu Y, Cai ZZ, Liang S, Niu YS, Miao YG

Abstract
Insect molting is an important developmental process of metamorphosis, which is initiated by molting hormone. The molting process includes the activation of dermal cells, epidermal cells separation, molting fluid secretion, the formation of new epidermis and old epidermis excoriation etc. Polyphenol oxidases (PPOs), dopa decarboxylase and acetyltransferase are necessary enzymes for this process. Traditionally, the phenol oxidase was considered as an enzyme for epidermal layer's tanning and melanization. This work suggested that polyphenol oxidases are one set of the key enzymes in molting, which closely related with the role of ecdysone in regulation of molting processes. The data showed that the expression peak of phenol oxidase in silkworm is higher during molting stage, and decreases after molting. The significant increase in the ecdysone levels of haemolymph was observed in the artificially fed silkworm larvae with ecdysone hormone. Consistently, the phenol oxidase expression was significantly elevated compared to the control. PPO1 RNAi induced phenol oxidase expression obviously declined in the silkworm larvae, and caused the pupae incomplete pupation. Overall, the results described that the phenol oxidase expression is regulated by the molting hormone, and is a necessary enzyme for the silkworm molting.

PMID: 23275200 [PubMed - as supplied by publisher]

zm-447439 rad001 ecdysone

Anti-neuropilin-1 (MNRP1685A): unexpected pharmacokinetic differences across species, from preclinical models to humans.

Anti-neuropilin-1 (MNRP1685A): unexpected pharmacokinetic differences across species, from preclinical models to humans.

Pharm Res. 2012 Sep;29(9):2512-21

Authors: Xin Y, Bai S, Damico-Beyer LA, Jin D, Liang WC, Wu Y, Theil FP, Joshi A, Lu Y, Lowe J, Maia M, Brachmann RK, Xiang H

Abstract
PURPOSE: To compare the pharmacokinetics (PK) of MNRP1685A, a human monoclonal antibody (mAb) against neuropilin-1 (NRP1), in mice, rats, monkeys, and cancer patients from a Phase I study to model with parallel linear and nonlinear clearances.
METHODS: Binding characteristics of MNRP1685A in different species were evaluated using surface plasmon resonance technology. PK profiles of MNRP1685A after single and/or multiple doses in different species were analyzed using population analysis. PK parameters were compared across species.
RESULTS: MNRP1685A binds to NRP1 in all four species tested. Consistent with the wide expression of NRP1, MNRP1685A demonstrated pronounced non-linear PK over a wide dose range. PK profiles are best described by a two-compartment model with parallel linear and nonlinear clearances. Model-derived PK parameters suggest similar in-vivo target expression levels and binding affinity to target across all species tested. However, compared to typical human/humanized mAbs, non-specific clearance of MNRP1685A was faster in mice, rats, and humans (60.3, 19.4, and 8.5�ml/day/kg), but not in monkeys (3.22�ml/day/kg).
CONCLUSIONS: Monkey PK properly predicted the target-mediated clearance of MNRP1685A but underestimated its non-specific clearance in humans. This unique PK property warrants further investigation of underlying mechanisms.

PMID: 22707361 [PubMed - indexed for MEDLINE]

chir-258 dovitinib dna-pk

2013年1月3日星期四

Pharmacokinetic and pharmacodynamic modeling of opioid-induced gastrointestinal side effects in patients receiving tapentadol IR and oxycodone IR.

Pharmacokinetic and pharmacodynamic modeling of opioid-induced gastrointestinal side effects in patients receiving tapentadol IR and oxycodone IR.

Pharm Res. 2012 Sep;29(9):2555-64

Authors: Xu XS, Etropolski M, Upmalis D, Okamoto A, Lin R, Nandy P

Abstract
PURPOSE: To understand the relationship between the risk of opioid-related gastrointestinal adverse effects (AEs) and exposure to tapentadol and oxycodone as well as its active metabolite, oxymorphone, using pharmacokinetic/pharmacodynamic models.
METHODS: The analysis was based on a study in patients with moderate-to-severe pain following bunionectomy. Population PK modeling was conducted to estimate population PK parameters for tapentadol, oxycodone, and oxymorphone. Time to AEs was analyzed using Cox proportional-hazards models.
RESULTS: Risk of nausea, vomiting, and constipation significantly increased with exposure to tapentadol or oxycodone/oxymorphone. However, elevated risk per drug exposure of AEs for tapentadol was ~3-4 times lower than that of oxycodone, while elevated AE risk per drug exposure of oxycodone was ~60 times lower than that for oxymorphone, consistent with reported in vitro receptor binding affinities for these compounds. Simulations show that AE incidence following administration of tapentadol IR is lower than that following oxycodone IR intake within the investigated range of analgesic noninferiority dose ratios.
CONCLUSIONS: This PK/PD analysis supports the clinical findings of reduced nausea, vomiting and constipation reported by patients treated with tapentadol, compared to patients treated with oxycodone.

PMID: 22618801 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

Pharmacokinetic and pharmacodynamic modeling of opioid-induced gastrointestinal side effects in patients receiving tapentadol IR and oxycodone IR.

Pharmacokinetic and pharmacodynamic modeling of opioid-induced gastrointestinal side effects in patients receiving tapentadol IR and oxycodone IR.

Pharm Res. 2012 Sep;29(9):2555-64

Authors: Xu XS, Etropolski M, Upmalis D, Okamoto A, Lin R, Nandy P

PMID: 22618801 [PubMed - indexed for MEDLINE]

rad001 ecdysone chir-258

Tetraploidization increases sensitivity to Aurora B kinase inhibition.

Tetraploidization increases sensitivity to Aurora B kinase inhibition.

Cell Cycle. 2012 Jul 1;11(13):2567-77

Authors: Marxer M, Foucar CE, Man WY, Chen Y, Ma HT, Poon RY

PMID: 22722494 [PubMed - in process]

ecdysone chir-258 dovitinib

A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma.

A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma.

Sci Transl Med. 2012 Jun 6;4(137):137ra75

Authors: Sivanand S, Pe�a-Llopis S, Zhao H, Kucejova B, Spence P, Pavia-Jimenez A, Yamasaki T, McBride DJ, Gillen J, Wolff NC, Morlock L, Lotan Y, Raj GV, Sagalowsky A, Margulis V, Cadeddu JA, Ross MT, Bentley DR, Kabbani W, Xie XJ, Kapur P, Williams NS, Brugarolas J

Abstract
Most anticancer drugs entering clinical trials fail to achieve approval from the U.S. Food and Drug Administration. Drug development is hampered by the lack of preclinical models with therapeutic predictive value. Herein, we report the development and validation of a tumorgraft model of renal cell carcinoma (RCC) and its application to the evaluation of an experimental drug. Tumor samples from 94 patients were implanted in the kidneys of mice without additives or disaggregation. Tumors from 35 of these patients formed tumorgrafts, and 16 stable lines were established. Samples from metastatic sites engrafted at higher frequency than those from primary tumors, and stable engraftment of primary tumors in mice correlated with decreased patient survival. Tumorgrafts retained the histology, gene expression, DNA copy number alterations, and more than 90% of the protein-coding gene mutations of the corresponding tumors. As determined by the induction of hypercalcemia in tumorgraft-bearing mice, tumorgrafts retained the ability to induce paraneoplastic syndromes. In studies simulating drug exposures in patients, RCC tumorgraft growth was inhibited by sunitinib and sirolimus (the active metabolite of temsirolimus in humans), but not by erlotinib, which was used as a control. Dovitinib, a drug in clinical development, showed greater activity than sunitinib and sirolimus. The routine incorporation of models recapitulating the molecular genetics and drug sensitivities of human tumors into preclinical programs has the potential to improve oncology drug development.

PMID: 22674553 [PubMed - indexed for MEDLINE]

dovitinib dna-pk coxinhibitors

Resistance artery mechanics and composition in angiotensin II-infused mice: effects of cyclooxygenase-1 inhibition.

Resistance artery mechanics and composition in angiotensin II-infused mice: effects of cyclooxygenase-1 inhibition.

Eur Heart J. 2012 Sep;33(17):2225-34

Authors: Virdis A, Colucci R, Neves MF, Rugani I, Aydinoglu F, Fornai M, Ippolito C, Antonioli L, Duranti E, Solini A, Bernardini N, Blandizzi C, Taddei S

Abstract
AIMS: The aim of this study was to investigate the role of cyclooxygenase (COX)-1 on vascular alterations in structure, mechanics, and extracellular matrix (ECM) components induced by angiotensin (Ang) II in mesenteric arteries from wild-type (WT) and COX-1 knockout (COX-1(-/-)) mice.
METHODS AND RESULTS: Animals were infused with vehicle or Ang II (400 ng/kg/min, s.c.) � SC-560 (COX-1 inhibitor), DFU (COX-2 inhibitor), or SQ-29548 (TP receptor antagonist). After 2 weeks, vessels were isolated and exposed to intraluminal pressures (3-140 mmHg, pressurized myograph) to determine mechanical properties. Angiotensin II-induced vascular hypertrophic remodelling in WT was reversed by SC-560 or SQ-29548, but unaffected by DFU. Angiotensin II increased vessel stiffness (P< 0.01), this effect being ameliorated by SC-560 or SQ-29548, but unmodified by DFU. Angiotensin II failed to modify vessel elasticity in COX-1(-/-) mice. In WT vessels, Ang II enhanced COX-1 immunostaining, induced collagen and fibronectin depositions and decreased elastin content (P< 0.01). These effects were reversed by SC-560 or SQ-29548, but unaffected by DFU. In COX-1(-/-) mice, Ang II did not affect ECM contents. In WT, Ang II increased COX-1 and decreased COX-2 expression, and enhanced the vascular release of 6-keto-PGF1? which was prevented by COX-1 blockade. Human coronary artery smooth muscle cells, incubated with Ang II, showed an increased expression of procollagen I, which was abrogated by SC-560 or SQ-29548.
CONCLUSION: Angiotensin II-induced alterations of resistance arteries in structure, mechanics, and ECM composition were prevented by COX-1 inhibition and TP receptor antagonism, indicating that Ang II-mediated vascular damage is mediated by COX-1-derived prostanoid prostacyclin, activating TP receptors.

PMID: 21606076 [PubMed - indexed for MEDLINE]

rad001 ecdysone chir-258

2013年1月2日星期三

Smg1 haploinsufficiency predisposes to tumor formation and inflammation.

Smg1 haploinsufficiency predisposes to tumor formation and inflammation.

Proc Natl Acad Sci U S A. 2012 Dec 31;

Authors: Roberts TL, Ho U, Luff J, Lee CS, Apte SH, Macdonald KP, Raggat LJ, Pettit AR, Morrow CA, Waters MJ, Chen P, Woods RG, Thomas GP, St Pierre L, Farah CS, Clarke RA, Brown JA, Lavin MF

Abstract
SMG1 is a member of the phosphoinositide kinase-like kinase family of proteins that includes ATM, ATR, and DNA-PK, proteins with known roles in DNA damage and cellular stress responses. SMG1 has a well-characterized role in nonsense-mediated decay as well as suggested roles in the DNA damage response, resistance to oxidative stress, regulation of hypoxic responses, and apoptosis. To understand the roles of SMG1 further, we generated a Genetrap Smg1 mouse model. Smg1 homozygous KO mice were early embryonic lethal, but Smg1 heterozygous mice showed a predisposition to a range of cancers, particularly lung and hematopoietic malignancies, as well as development of chronic inflammation. These mice did not display deficiencies in known roles of SMG1, including nonsense-mediated decay. However, they showed elevated basal tissue and serum cytokine levels, indicating low-level inflammation before the development of tumors. Smg1 heterozygous mice also showed evidence of oxidative damage in tissues. These data suggest that the inflammation observed in Smg1 haploinsufficiency contributes to susceptibility to cancer and that Smg1-deficient animals represent a model of inflammation-enhanced cancer development.

PMID: 23277562 [PubMed - as supplied by publisher]

chir-258 dovitinib dna-pk

Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis.

Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis.

J Transl Med. 2012 Dec 10;10(1):245

Authors: Chen ZY, Shi M, Peng LX, Wei W, Li XJ, Guo ZX, Li SH, Zhong C, Qian CN, Guo RP

Abstract
ABSTRACT: BACKGROUND: Dovitinib is a receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptors and platelet-derived growth factor receptor beta. Dovitinib is currently in clinical trials for the treatment of hepatocellular carcinoma (HCC). METHOD: In this study, we used five HCC cell lines and five endothelial cell lines to validate molecular and cellular targets of dovitinib. RESULTS: Tumor growth and pulmonary metastasis were significantly suppressed in an orthotopic HCC model. Immunoblotting revealed that among known dovitinib targets, only PDGFR-beta was expressed in two HCC cell lines, while four of five endothelial lines expressed PDGFR-beta, FGFR-1, and VEGFR-2. Dovitinib inhibited endothelial cell proliferation and motility at 0.04 mumol/L, a pharmacologically relevant concentration; it was unable to inhibit the proliferation or motility of HCC cells at the same concentration. Immunohistochemical analyses showed that dovitinib significantly decreased the microvessel density of xenograft tumors, inhibiting proliferation and inducing apoptosis in HCC cells. CONCLUSION: Our findings indicate that dovitinib inhibits HCC growth and metastasis preferentially through an antiangiogenic mechanism, not through direct targeting of HCC cells.

PMID: 23228017 [PubMed - as supplied by publisher]

chir-258 dovitinib dna-pk

Biopsy Gleason score and the duration of testosterone suppression among men treated with external beam radiation and 6 months of combined androgen blockade.

Biopsy Gleason score and the duration of testosterone suppression among men treated with external beam radiation and 6 months of combined androgen blockade.

BJU Int. 2012 Nov;110(9):1252-6

Authors: Martin NE, Chen MH, Nguyen PL, Beard CJ, Loffredo MJ, Kantoff PW, D'Amico AV

Abstract
UNLABELLED: Study Type - Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? The return of testosterone to normal levels following short-course androgen blockade in prostate cancer is variable. Factors associated with a longer time to recovery include older age and lower baseline testosterone level. In this study, we found that among men treated with 6 months of combined androgen blockade and radiation therapy, higher biopsy Gleason grade was associated with a shorter time to testosterone normalization.
OBJECTIVE: ? To determine whether the biopsy Gleason score is associated with duration of testosterone suppression following 6 months of combined androgen blockade (CAB) and radiation therapy (RT) in men with prostate cancer (PCa).
PATIENTS AND METHODS: ? The study cohort consisted of 221 men with PCa treated with RT and 6 months of CAB between 1996 and 2005. ? We defined the duration of testosterone suppression as the time between the last day of CAB and the date the testosterone returned to ? 252 ng/dL. We used Cox regression multivariable analysis to relate biopsy Gleason score to duration of testosterone suppression following cessation of CAB.
RESULTS: ? A biopsy Gleason score of 8-10 had an adjusted hazard ratio (AHR) of 1.56 (95% confidence interval [CI] 1.04, 2.34; P= 0.03) for a shorter time to testosterone normalization relative to Gleason 6. Specifically, the 51 men with biopsy Gleason score of 8-10 had a median time to testosterone normalization of 17.0 months compared with 22.1 months and 23.8 months for those with biopsy Gleason ? 6 and 7, respectively. ? Increasing age was significantly associated with a longer duration of testosterone suppression (AHR of 0.95 [95% CI 0.92, 0.97; P < 0.001]) as was a higher baseline PSA (AHR 0.82 [95% CI 0.69, 0.97; P= 0.02]).
CONCLUSION: ? A biopsy Gleason score of 8-10 was associated with a shorter period of testosterone suppression following 6 months of CAB and RT. These data are consistent with the hypothesis that a factor released from high-grade PCa cells may impact on testosterone production.

PMID: 22564379 [PubMed - indexed for MEDLINE]

chir-258 dovitinib dna-pk

Phenol oxidase is a necessary enzyme for the silkworm molting which is regulated by molting hormone.

Phenol oxidase is a necessary enzyme for the silkworm molting which is regulated by molting hormone.

Mol Biol Rep. 2012 Dec 29;

Authors: Wang MX, Lu Y, Cai ZZ, Liang S, Niu YS, Miao YG

PMID: 23275200 [PubMed - as supplied by publisher]

dovitinib dna-pk coxinhibitors

Safety of Everolimus by Treatment Duration in�Patients With Advanced Renal Cell Cancer in an Expanded Access Program.

Safety of Everolimus by Treatment Duration in�Patients With Advanced Renal Cell Cancer in an Expanded Access Program.

Urology. 2013 Jan;81(1):143-9

Authors: van den Eertwegh AJ, Karakiewicz P, Bavbek S, Rha SY, Bracarda S, Bahl A, Ou YC, Kim D, Panneerselvam A, Anak O, Gr�nwald V

Abstract
OBJECTIVE: To retrospectively analyze the effects of treatment duration on outcomes of everolimus treatment of patients in the RAD001 Expanded-Access Clinical Trial in RCC (REACT) program.
METHODS: Patients with metastatic renal cell carcinoma refractory to vascular endothelial growth factor receptor-tyrosine kinase inhibitor received everolimus (10 mg once daily), with dosing interruption or modifications allowed for toxicity. All serious and grade 3/4 adverse events and grade 1/2 adverse events leading to a change in drug administration were reported. Tumor response was evaluated using Response Evaluation Criteria In Solid Tumors.
RESULTS: The study stratified 1367 evaluable patients into treatment duration groups of�<3 months,�?3 and�<6 months,�?6 months and�<1 year, and�?1 year. Pneumonia, noninfectious pneumonitis, and hyperglycemia occurred more frequently in patients receiving everolimus for�?1 year but did not result in treatment discontinuations. First occurrence of adverse events presented early in the treatment course for most patients. Treatment duration of�?6 months was associated with improved disease control rates.
CONCLUSION: Everolimus is well tolerated in patients with metastatic renal cell carcinoma for treatment durations�?1 year and not associated with cumulative toxicity.

PMID: 23273080 [PubMed - in process]

dna-pk coxinhibitors c-met inhibitors

2013年1月1日星期二

JAK-STAT pathway modulates the roles of iNOS and COX-2 in the cytoprotection of early phase of hydrogen peroxide preconditioning against apoptosis induced by oxidative stress.

JAK-STAT pathway modulates the roles of iNOS and COX-2 in the cytoprotection of early phase of hydrogen peroxide preconditioning against apoptosis induced by oxidative stress.

Neurosci Lett. 2012 Nov 7;529(2):166-71

Authors: Yu H, Liu Z, Zhou H, Dai W, Chen S, Shu Y, Feng J

Abstract
Our previous studies have demonstrated that preconditioning with hydrogen peroxide (H(2)O(2)) activated the JAK-STAT pathway that played an important role in the cytoprotection, and inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mediated the late phase of cytoprotection induced by high concentration of H(2)O(2) after preconditioning. Here we sought to identify the downstream targets of the JAK-STAT axis that mediated H(2)O(2) preconditioning and the expression of iNOS and COX-2 in the early phase of H(2)O(2) preconditioning. It was shown that (1) Preconditioning with H(2)O(2) at 100 ?mol/L for 90 min in PC12 cells induced significant expression of iNOS and COX-2. (2) Pretreatment with the iNOS inhibitor AG (10 ?mol/L) or the COX-2 inhibitor NS-398 (10 ?mol/L) respectively 20min before H(2)O(2) preconditioning not only inhibits the increased expression of iNOS or COX-2 but also abrogates the protective effects of H(2)O(2) preconditioning against apoptosis induced by oxidative stress. (3) Pretreatment with the JAK inhibitor AG-490 (10 ?mol/L) 20 min before H(2)O(2) preconditioning obviously inhibits the up-regulation of iNOS or COX-2 induced by H(2)O(2) preconditioning. These results suggested that JAK-STAT pathway modulates the roles of iNOS and COX-2 in the cytoprotection of early phase of H(2)O(2) preconditioning.

PMID: 22995181 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

Safety and efficacy of everolimus after kidney and hematopoietic stem cell transplantation.

Safety and efficacy of everolimus after kidney and hematopoietic stem cell transplantation.

Ann Transplant. 2012 Dec 31;17(4):52-8

Authors: Keller F, Wiesner S, Bunjes D, Hartmann B, Schmitt M

Abstract
Background: The aim of this retrospective study was to investigate the efficacy of everolimus at our institution and to report incidence and type of side effects in patients who underwent kidney transplantation or hematopoietic stem cell transplantation (HSCT). Material/Methods: Electronic medical records were evaluated for 122 patients (76 men and 46 women) treated with everolimus between January 2000 and January 2009. Of these patients, 81 had undergone kidney transplantation (mean age: 56�12 years) and 41 patients were treated with HSCT (mean age: 47�11 years). Results: Everolimus was discontinued in a total of 53% of patients (n=64) with no difference observed in kidney transplant recipients vs. stem cell transplanted patients (p=0.85). In one half of the patients, cessation of the drug was due to a lack of long-term efficacy (n=32). In the other half, everolimus was discontinued due to side effects (n=32). However, patients with side effects had no elevated everolimus concentrations (5.5�2.3 vs. 5.2�1.7 ng/ml; p=0.39). Pneumonitis (n=5) or proteinuria over 1.5 g per day (n=13) were only observed in kidney transplant patients, while polyomavirus-induced cystitis (n=3) and thrombotic thrombocytopenic purpura (n=7) were only observed in stem cell transplanted patients. Conclusions: Everolimus was an effective immunosuppressive agent in half of the patients. A quarter of all patients developed side effects resulting in discontinuation of the drug. The profile of side effects in kidney recipients clearly differs from hematopoietic stem cell transplanted patients.

PMID: 23274324 [PubMed - in process]

ecdysone chir-258 dovitinib

Comparison of Paclitaxel-Eluting Stents (Taxus) and Everolimus-Eluting Stents (Xience) in Left Main Coronary Artery Disease With 3 Years Follow-Up (from the ESTROFA-LM Registry).

Comparison of Paclitaxel-Eluting Stents (Taxus) and Everolimus-Eluting Stents (Xience) in Left Main Coronary Artery Disease With 3 Years Follow-Up (from the ESTROFA-LM Registry).

Am J Cardiol. 2012 Dec 27;

Authors: De la Torre Hernandez JM, Alfonso F, Recalde AS, Jimenez Navarro MF, Perez de Prado A, Hernandez F, Abdul-Jawad Altisent O, Roura G, Camarero TG, Elizaga J, Rivero F, Gimeno F, Calvi�o R, Moreu J, Bosa F, Rumoroso JR, Bullones JA, Gallardo A, Fernandez Diaz JA, Ruiz Arroyo JR, Aragon V, Masotti M, ESTROFA-LM Study Group

Abstract
Evidence regarding therapy with drug-eluting stents in the left main coronary artery (LM) is based mostly on trials performed with first-generation drug-eluting stents. The aim of this study was to evaluate long-term clinical outcomes after treatment for unprotected LM disease with paclitaxel-eluting stents (PES) and everolimus-eluting stents (EES). The ESTROFA-LM is a multicenter retrospective registry including consecutive patients with unprotected LM disease treated with PES or EES. A total of 770 patients have been included at 21 centers, 415 with treated PES and 355 with EES. Treatment with 2 stents was more frequent with PES (17% vs 10.4%, p�= 0.007), whereas intravascular ultrasound was more frequently used with EES (35.2% vs 26%, p�= 0.006). The 3-year death and infarction survival rates were 86.1% for PES and 87.3% for EES (p�= 0.50) and for death, infarction, and target lesion revascularization were 83.6% versus 82% (p�= 0.60), respectively. Definite or probable thrombosis was 1.6% for PES and 1.4% for EES (p�= 0.80). The use of 2 stents, age, diabetes, and acute coronary syndromes were independent predictors of mortality. In the subgroup of distal lesions, the use of intravascular ultrasound was an independent predictor of better outcome. Comparison of propensity score-matched groups did not yield differences between the 2 stents. In conclusion, the results of this multicenter registry show comparable safety and efficacy at 3 years for PES and EES in the treatment of LM disease. The use of bifurcation stenting techniques in distal lesions was a relevant independent predictor for events. The use of intravascular ultrasound appears to have a positive impact on patients treated for LM distal disease.

PMID: 23273715 [PubMed - as supplied by publisher]

dovitinib dna-pk coxinhibitors

Tetraploidization increases sensitivity to Aurora B kinase inhibition.

Tetraploidization increases sensitivity to Aurora B kinase inhibition.

Cell Cycle. 2012 Jul 1;11(13):2567-77

Authors: Marxer M, Foucar CE, Man WY, Chen Y, Ma HT, Poon RY

PMID: 22722494 [PubMed - in process]

rad001 ecdysone chir-258

2012年12月31日星期一

A translocator protein ligand PK11195 shows antigrowth activity in human choriocarcinoma cells.

A translocator protein ligand PK11195 shows antigrowth activity in human choriocarcinoma cells.

Tumour Biol. 2012 Oct;33(5):1505-10

Authors: Takai N, Kira N, Ishii T, Yoshida T, Nishida M, Nishida Y, Nasu K, Takano M, Midori H, Koga S, Narahara H

Abstract
The potential anticancer agent 1-(2-chlorophenyl-N-methylpropyl)-3-isoquinolinecarboxamide (PK11195), a translocator protein ligand (initially described as a ligand for the peripheral benzodiazepine receptor), induces apoptosis in some lines of human tumor cells. We investigated the effect of PK11195 in the choriocarcinoma cell line, BeWo. BeWo cells were treated with various concentrations of PK11195, and changes in cell growth, the cell cycle, apoptosis, and related parameters were examined. A WST-1 assay showed that BeWo cells were sensitive to the growth inhibitory effect of PK11195. In contrast, the nonsite selective ligand diazepam has a little effect on these cells. Cell cycle analysis indicated that exposure to PK11195 decreased the proportion of cells in the S phase and increased the proportion in the G0/G1 phases of the cell cycle. Induction of apoptosis was confirmed by Annexin V staining of externalized phosphatidylserine, by the loss of mitochondrial transmembrane potential, and by antibodies directed against histones from fragmented DNA. This induction occurred in conjunction with the altered expression of genes related to cell growth, malignant phenotype, and apoptosis. These results suggest that PK11195 may serve as a therapeutic agent for the treatment of choriocarcinoma.

PMID: 22528948 [PubMed - indexed for MEDLINE]

dovitinib dna-pk coxinhibitors

A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma.

A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma.

Sci Transl Med. 2012 Jun 6;4(137):137ra75

PMID: 22674553 [PubMed - indexed for MEDLINE]

dovitinib dna-pk coxinhibitors

Constitutively active c-Met kinase in PC-3 cells is autocrine-independent and can be blocked by the Met kinase inhibitor BMS-777607.

Constitutively active c-Met kinase in PC-3 cells is autocrine-independent and can be blocked by the Met kinase inhibitor BMS-777607.

BMC Cancer. 2012;12:198

Authors: Dai Y, Siemann DW

Abstract
BACKGROUND: The c-Met receptor tyrosine kinase is aberrantly activated in many solid tumors. In a prior study we showed that prostate cancer PC-3 cells exhibit constitutively activated c-Met without exogenous hepatocyte growth factor (HGF); however whether this characteristic is due to an endogenous HGF/c-Met autocrine loop remains controversial. In the current study we examined the response of PC-3 cells to an anti-HGF neutralizing antibody or a small molecule Met kinase inhibitor (BMS-777607).
METHODS: Cell scattering was tested by monitoring cell morphology after HGF stimulation. Cell migration was examined by both "wound-healing" and transwell assasy and invasion was detected by Matrigel-coated transwell assay. Proliferation, survival and anoikis were determined by MTT, colony formation and trypan blue exclusion assay, respectively. Gene and protein expression were assessed by real-time PCR and Western blot, respectively.
RESULTS: Although HGF mRNA could be detected in PC-3 cells, the molecular weight of secreted "HGF" protein was inconsistent with the functional recombinant HGF. Furthermore, conditioned medium from PC-3 cell cultures was ineffective at triggering either motogenic behavior or c-Met signaling in DU145, another prostate cancer cell line expressing c-Met but lacking basal c-Met activation. PC-3 cells also were not responsive to the anti-HGF neutralizing antibody in experiments assessing proliferation, migration, or c-Met signaling. BMS-777607 treatment with micromolar doses nonetheless led to significant inhibition of multiple PC-3 cell functions including proliferation, clonogenicity, migration and invasion. At the molecular level, BMS-777607 suppressed autophosphorylated c-Met and downstream c-Src and Akt pathways.
CONCLUSIONS: These results suggest that the constitutive c-Met activation in PC-3 is independent of autocrine stimulation. Because PC-3 cells were responsive to BMS-777607 but not the anti-HGF antibody, the findings also indicate that under circumstances where c-Met is constitutively hyperactive in the absence of functional HGF, targeting the c-Met receptor remains a viable therapeutic option to impede cancer progression.

PMID: 22639908 [PubMed - indexed for MEDLINE]

dovitinib dna-pk coxinhibitors

The Mammalian target of rapamycin inhibitors in breast cancer: current evidence and future directions.

The Mammalian target of rapamycin inhibitors in breast cancer: current evidence and future directions.

Anticancer Res. 2013 Jan;33(1):21-8

Authors: Malaguti P, Vari S, Cognetti F, Fabi A

Abstract
Mammalian target of rapamycin (mTOR) is a crucial mediator of tumor progression and may be a promising target in a significant proportion of patients with breast cancer. More specifically, the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mTOR pathway plays a critical role in multiple cellular functions including metabolism, proliferation, growth and survival. This pathway is higly active in many types of cancer and is linked to resistance to many types of therapy. Direct blockade of the mTOR pathway is a new area in breast cancer therapy, with the potential to modulate growth factor- and estrogen-dependent and estrogen-independent pathways, which contribute to the pathogenesis and progression of tumors. Thus, inhibitors of mTOR are of interest as potential therapeutic agents for patients with breast cancer, everolimus and temsirolimus being the main representatives of this category. This review of the literature analyzes the available data emerging from trials and evaluates the efficacy and safety of mTOR inhibitors in all subtypes of breast cancer.

PMID: 23267124 [PubMed - in process]

chir-258 dovitinib dna-pk

Tetraploidization increases sensitivity to Aurora B kinase inhibition.

Tetraploidization increases sensitivity to Aurora B kinase inhibition.

Cell Cycle. 2012 Jul 1;11(13):2567-77

Authors: Marxer M, Foucar CE, Man WY, Chen Y, Ma HT, Poon RY

PMID: 22722494 [PubMed - in process]

chir-258 dovitinib dna-pk

2012年12月30日星期日

The Mammalian target of rapamycin inhibitors in breast cancer: current evidence and future directions.

The Mammalian target of rapamycin inhibitors in breast cancer: current evidence and future directions.

Anticancer Res. 2013 Jan;33(1):21-8

Authors: Malaguti P, Vari S, Cognetti F, Fabi A

PMID: 23267124 [PubMed - in process]

rad001 ecdysone chir-258

DREF is involved in the steroidogenesis via regulation of shadow gene.

DREF is involved in the steroidogenesis via regulation of shadow gene.

Am J Cancer Res. 2012;2(6):714-25

Authors: Park JS, Choi YJ, Thao DT, Kim YS, Yamaguchi M, Yoo MA

Abstract
The Drosophila DNA replication-related element-binding factor (dDREF) has been identified as a master regulator of cell proliferation-related genes via its binding to the DRE sequence, 5'-TATCGATA. However, the biological roles of DREF are still to be clarified. Here, we show that DREF mutant females have steroid hormone ecdysone-deficient phenotypes, such as the loss of vitellogenic egg chambers. Furthermore, DREF knockdown in the prothoracic gland of larva prevented pupation and this was rescued via 20-hydroxyecdysone treatment. We found a DRE-like sequence (-625 to -632) in the 5'-flanking region of the Drosophila shadow gene, which catalyzes the conversion of 2-deoxyecdysone to ecdysone, and demonstrated that shadow is a novel target gene of dDREF using quantitative RT-PCR and Chip assays. In addition, we show that the level of dDREF protein correlated with age-related changes in the level of shadow mRNA in the ovaries of wild-type flies. Taken together, our data indicate that dDREF plays a key role in steroid synthesis via regulation of the shadow gene.

PMID: 23226617 [PubMed]

dovitinib dna-pk coxinhibitors