5-alpha-reductase: 2013-03-24

2013年3月30日星期六

Bafilomycin A1 activates HIF-dependent signalling in human colon cancer cells via mitochondrial uncoupling.

Bafilomycin A1 activates HIF-dependent signalling in human colon cancer cells via mitochondrial uncoupling.

Biosci Rep. 2012 Dec;32(6):587-95

Authors: Zhdanov AV, Dmitriev RI, Papkovsky DB

Abstract
Mitochondrial uncoupling is implicated in many patho(physiological) states. Using confocal live cell imaging and an optical O2 sensing technique, we show that moderate uncoupling of the mitochondria with plecomacrolide Baf (bafilomycin A1) causes partial depolarization of the mitochondria and deep sustained deoxygenation of human colon cancer HCT116 cells subjected to 6% atmospheric O2. A decrease in iO2 (intracellular O2) to 0-10�?M, induced by Baf, is sufficient for stabilization of HIFs (hypoxia inducible factors) HIF-1? and HIF-2?, coupled with an increased expression of target genes including GLUT1 (glucose transporter 1), HIF PHD2 (prolyl hydroxylase domain 2) and CAIX (carbonic anhydrase IX). Under the same hypoxic conditions, treatment with Baf causes neither decrease in iO2 nor HIF-? stabilization in the low-respiring HCT116 cells deficient in COX (cytochrome c-oxidase). Both cell types�display equal capacities for HIF-? stabilization by hypoxia mimetics DMOG (dimethyloxalylglycine) and CoCl2, thus suggesting that the effect of Baf under hypoxia is driven mainly by mitochondrial respiration. Altogether, by activating HIF signalling under moderate hypoxia, mitochondrial uncoupling can play an important regulatory role in colon cancer metabolism and modulate adaptation of cancer cells to natural hypoxic environments.

PMID: 22943412 [PubMed - indexed for MEDLINE]

dovitinib dna-pk coxinhibitors

Cytomegalovirus-Positive Corneal Stromal Edema With Keratic Precipitates After Penetrating Keratoplasty: A Case-Control Study.

Cytomegalovirus-Positive Corneal Stromal Edema With Keratic Precipitates After Penetrating Keratoplasty: A Case-Control Study.

Cornea. 2013 Mar 27;

Authors: Chee SP, Jap A, Wen Ling EC, Ti SE

Abstract
PURPOSE:: To identify differences between cytomegalovirus (CMV)-positive and CMV-negative eyes presenting as suspected endothelial graft rejection after penetrating keratoplasty (PK). METHODS:: A retrospective consecutive case-control series. Aqueous humor samples of all eyes with corneal stromal edema and keratic precipitates (KPs) after PK, seen at the Singapore National Eye Centre from 2007 to 2010, were analyzed for CMV DNA by polymerase chain reaction. Their charts were reviewed for demographic data, medical and ocular history, best-corrected visual acuity, intraocular pressure, anterior segment clinical findings, and therapy. RESULTS:: Of 11 eligible eyes (11 patients), 7 were CMV positive. All eyes were negative for herpes simplex virus and varicella zoster virus. The 2 groups were similar in age, gender, and previous ocular surgery. The main differences were the presence of extensive heavily pigmented KPs, Descemet membrane folds, and the absence of vascularization of the donor in CMV-positive eyes (100% vs. 0%, P = 0.003, Fisher exact test). All the CMV-positive eyes were treated with ganciclovir (5 systemic, 2 topical), and the control eyes received immunosuppression. However, all the grafts failed. Best-corrected visual acuity at the last visit was worse than 20/400 in all except 1 control eye, which had a follow-up of 30 months. CONCLUSIONS:: There is a high prevalence of CMV infection in eyes that develop corneal stromal edema with KPs after PK. Heavy endothelial pigmentation, Descemet membrane folds, and the absence of donor vascularization may aid in the diagnosis of CMV in the event that aqueous analysis is not possible.

PMID: 23538617 [PubMed - as supplied by publisher]

chir-258 dovitinib dna-pk

Molecular Targets in the Discovery and Development of Novel Antimetastatic Agents: Current Progress and Future Prospects.

Molecular Targets in the Discovery and Development of Novel Antimetastatic Agents: Current Progress and Future Prospects.

Clin Exp Pharmacol Physiol. 2013 Mar 27;

Authors: Szinwong M, Sidek SM, Mahmud R, Stanslas J

Abstract
Tumour invasion and metastasis have been recognised as major causal factors in the morbidity and mortality among cancer patients. Many advances in the knowledge of cancer metastasis have yielded an impressive array of attractive drug targets, including enzymes, receptors, and multiple signalling pathways. This review summarizes the molecular pathogenesis of metastasis and the identification of novel molecular targets utilised in the discovery of antimetastatic agents. Several promising targets have been highlighted, which include receptor tyrosine kinases (RTKs), effector molecules involved in angiogenesis, matrix metalloproteinases (MMPs), urokinase plasminogen activator (uPA), adhesion molecules and their receptors, signalling pathways (eg, phosphatidylinositol 3-kinase (PI3K), phospholipase C?1 (PLC?1), MAP kinases (MAPK), c-Src kinase, c-Met kinases and heat shock protein (HSP 90)). The discovery and development of potential novel therapeutics for each of the targets are also discussed in this review. Among these, the most promising agents that showed remarkable clinical outcome are anti-angiogenic agents (eg, bevacizumab). Newer agents, such as c-Met kinase inhibitors, are still undergoing preclinical studies and have yet had their clinical efficacy to be proven. Some therapeutics, such as first-generation MMP inhibitors (MMPIs, eg, marimastat) and more selective versions of them (eg, prinomastat, tanomastat), have undergone clinical trials. Unfortunately, these drugs produced serious adverse effects and led to premature termination of their development. In the future, third-generation MMPIs and inhibitors of signalling pathways and adhesion molecules could form valuable novel classes of drugs in the anticancer armamentarium to combat metastasis. � 2013 The Authors Clinical and Experimental Pharmacology and Physiology � 2013 Wiley Publishing Asia Pty Ltd.

PMID: 23534409 [PubMed - as supplied by publisher]

coxinhibitors c-met inhibitors zm-447439

Role of prostaglandin receptor EP2 in the regulations of cancer cell proliferation, invasion, and inflammation.

Role of prostaglandin receptor EP2 in the regulations of cancer cell proliferation, invasion, and inflammation.

J Pharmacol Exp Ther. 2013 Feb;344(2):360-7

Authors: Jiang J, Dingledine R

Abstract
Population studies, preclinical, and clinical trials suggest a role for cyclooxygenase-2 (COX-2, PTGS2) in tumor formation and progression. The downstream prostanoid receptor signaling pathways involved in tumorigenesis are poorly understood, although prostaglandin E2 (PGE(2)), a major COX-2 metabolite which is usually upregulated in the involved tissues, presumably plays important roles in tumor biology. Taking advantage of our recently identified novel selective antagonist for the EP2 (PTGER2) subtype of PGE(2) receptor, we demonstrated that EP2 receptor activation could promote prostate cancer cell growth and invasion in vitro, accompanied by upregulation of the tumor-promoting inflammatory cytokines, such as IL-1? and IL-6. Our results suggest the involvement of prostaglandin receptor EP2 in cancer cell proliferation and invasion possibly via its inflammatory actions, and indicate that selective blockade of the PGE(2)-EP2 signaling pathway via small molecule antagonists might represent a novel therapy for tumorigenesis.

PMID: 23192657 [PubMed - indexed for MEDLINE]

dna-pk coxinhibitors c-met inhibitors

Single-dose safety and pharmacokinetic evaluation of fluorocoxib A: pilot study of novel cyclooxygenase-2-targeted optical imaging agent in a canine model.

Single-dose safety and pharmacokinetic evaluation of fluorocoxib A: pilot study of novel cyclooxygenase-2-targeted optical imaging agent in a canine model.

J Biomed Opt. 2012 Nov;17(11):116002

Authors: Cekanova M, Uddin MJ, Legendre AM, Galyon G, Bartges JW, Callens A, Martin-Jimenez T, Marnett LJ

Abstract
We evaluated preclinical single-dose safety, pharmacokinetic properties, and specific uptake of the new optical imaging agent fluorocoxib A in dogs. Fluorocoxib A, N-[(5-carboxy-X-rhodaminyl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide, selectively binds and inhibits the cyclooxygenase-2 (COX-2) enzyme, which is overexpressed in many cancers. Safety pilot studies were performed in research dogs following intravenous (i.v.) administration of 0.1 and 1??mg/kg fluorocoxib A. Blood and urine samples collected three days after administration of each dose of fluorocoxib A revealed no evidence of toxicity, and no clinically relevant adverse events were noted on physical examination of exposed dogs over that time period. Pharmacokinetic parameters were assessed in additional research dogs from plasma collected at several time points after i.v. administration of fluorocoxib A using high-performance liquid chromatography analysis. The pharmacokinetic studies using 1??mg/kg showed a peak of fluorocoxib A (92�28??ng/ml) in plasma collected at 0.5 h. Tumor specific uptake of fluorocoxib A was demonstrated using a dog diagnosed with colorectal cancer expressing COX-2. Our data support the safe single-dose administration and in vivo efficacy of fluorocoxib A, suggesting a high potential for successful translation to clinical use as an imaging agent for improved tumor detection in humans.

PMID: 23117797 [PubMed - indexed for MEDLINE]

ecdysone chir-258 dovitinib

2013年3月29日星期五

Protein phosphatase 2A and DNA-dependent protein kinase are involved in mediating rapamycin-induced Akt phosphorylation.

Protein phosphatase 2A and DNA-dependent protein kinase are involved in mediating rapamycin-induced Akt phosphorylation.

J Biol Chem. 2013 Mar 27;

Authors: Li Y, Wang X, Yue P, Tao H, Ramalingam SS, Owonikoko TK, Deng X, Wang Y, Fu H, Khuri FR, Sun SY

Abstract
Inhibition of mammalian target of rapamycin complex 1 (mTORC1), for example with rapamycin, increases Akt phosphorylation while inhibiting mTORC1 signaling. However the underlying mechanisms have not been fully elucidated. The current study has uncovered a previously unknown mechanism underlying rapamycin induced Akt phosphorylation involving protein phosphatase 2A (PP2A) dependent DNA protein kinase (DNA-PK) activation. In several cancer cell lines, inhibition of PP2A with okadaic acid, fostriecin, small T antigen, or PP2A knockdown abrogated rapamycin induced Akt phosphorylation, and rapamycin increased PP2A activity. Chemical inhibition of DNA-PK, knockdown or deficiency of DNA-PK catalytic subunit (DNA-PKcs), or knockout of the DNA-PK component Ku86 inhibited rapamycin induced Akt phosphorylation. Exposure of cancer cells to rapamycin increased DNA-PK activity and gene silencing mediated PP2A inhibition attenuated rapamycin-induced DNA-PK activity. Collectively these results suggest that rapamycin induces PP2A dependent and DNA-PK mediated Akt phosphorylation. Accordingly, simultaneous inhibition of mTOR and DNA-PK did not stimulate Akt activity and synergistically inhibited the growth of cancer cells both in vitro and in vivo. Thus, our findings also suggest a novel strategy to enhance mTOR targeted cancer therapy by cotargeting DNA-PK.

PMID: 23536185 [PubMed - as supplied by publisher]

dna-pk coxinhibitors c-met inhibitors

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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Molecular Targets in the Discovery and Development of Novel Antimetastatic Agents: Current Progress and Future Prospects.

Molecular Targets in the Discovery and Development of Novel Antimetastatic Agents: Current Progress and Future Prospects.

Clin Exp Pharmacol Physiol. 2013 Mar 27;

Authors: Szinwong M, Sidek SM, Mahmud R, Stanslas J

PMID: 23534409 [PubMed - as supplied by publisher]

dovitinib dna-pk coxinhibitors

Deciphering the systems biology of mTOR inhibition by integrative transcriptome analysis.

Deciphering the systems biology of mTOR inhibition by integrative transcriptome analysis.

Curr Pharm Des. 2013 Mar 19;

Authors: Domhan S, Schwager C, Wei Q, Muschal S, Sommerer C, Morath C, Wick W, Maercker C, Debus J, Zeier M, Huber PE, Abdollahi A

Abstract
The mTOR signaling plays an integral role in cellular homeostasis controlling the transition between the catabolic and anabolic states. Originally approved as immunosuppressive agents preventing allograft rejection, inhibitors of mTOR signaling have recently entered the arena of cancer therapy. Using rapamycin derivative (RAD001) as a prototype inhibitor, we aimed to systematically analyze the molecular mechanisms underlying the pleiotropic effects of mTOR signaling. Using proliferation- and clonogenic survival assays, a preferential sensitivity of microvascular endothelial cells (HDMVEC) followed by fibroblasts and U87 gliblastoma to RAD001 treatment was found. In contrast, lung- and prostate tumor cells demonstrated relative resistance against RAD001 treatment. In co-culture with fibroblasts, RAD001 exerted potent antiangiogenic effects by inhibiting endothelial cell tube formation. Further, RAD001 treatment efficiently prevented tumor growth in U87 tumor xenografts. Integrative transcriptome analysis was performed to decipher the molecular mechanism underlying RAD001 -induced anti-tumor and antiangiogenic effects. The predominant expression pattern was downregulation of genes after RAD001 treatment in all three sensitive cell types. Among the RAD001 downregulated genes, a transcriptional network was discovered enriched for genes related to angiogenesis processes and extracellular matrix remodeling, e.g., VEGF, HIF1A, CXCLs, IL6, FN, PAI-1 or NRP1. Of note, key components of PI3K upstream (PDK1) as well as mTORC2 downstream signaling (SGK1, NDRG) were downregulated by RAD001. Decreased expression of IMPDH and 139 common gene targets between mycophenolic acid and RAD001 suggested in part shared mechanisms underlying their antiangiogenic and immunosuppressive effects. In summary, key genetic participants governing anti-tumor and anti-angiogenic effects of mTOR inhibition were identified.

PMID: 23530502 [PubMed - as supplied by publisher]

chir-258 dovitinib dna-pk

Cytotoxic tetraprenylated alkaloids from the South China Sea gorgonian Euplexaura robusta.

Cytotoxic tetraprenylated alkaloids from the South China Sea gorgonian Euplexaura robusta.

Chem Biodivers. 2012 Oct;9(10):2218-24

Authors: Zhang JR, Li PL, Tang XL, Qi X, Li GQ

Abstract
Nine achiral tetraprenylated alkaloids, including three new compounds, named malonganenones I-K (1-3, resp.), together with six known analogs, 4-9, were isolated from the gorgonian Euplexaura robusta collected from Weizhou Island of Guangxi Province, China. The structures of compounds 1-3 were elucidated by extensive spectral analyses, especially of their 1D- and 2D-NMR data. Compounds 1, 4, 6, and 7 showed moderate cytotoxicities against K562 and HeLa tumor cell lines with IC(50) values ranging from 0.35 to 10.82 ?M. Compound 6 also showed moderate inhibitory activity against c-Met kinase at a concentration of 10 ?M.

PMID: 23081922 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

2013年3月28日星期四

An association between the PTGS2 rs5275 polymorphism and colorectal cancer risk in families with inherited non-syndromic predisposition.

An association between the PTGS2 rs5275 polymorphism and colorectal cancer risk in families with inherited non-syndromic predisposition.

Eur J Hum Genet. 2013 Mar 27;

Authors: Ross J, Lockett L, Brookes D, Tabor B, Duesing K, Buckley M, Lockett T, Molloy P, Macrae F, Young G, Blanco I, Capella G, Hannan GN

Abstract
Recently our group completed a genome-wide linkage study investigating Australian and Spanish families with inherited risk of colorectal cancer (CRC). A minor linkage peak from that study located on chromosome 1 correlates with the location of a known CRC risk-modifying gene, prostaglandin synthase (PTGS2). PTGS2 encodes the inducible prostaglandin synthase enzyme cyclooxygenase-2 (COX-2). Prostaglandins are implicated in the initiation of carcinogenesis and progression of tumours. Sequencing of PTGS2 in a small subset of affected individuals identified a high frequency of the minor C allele of single nucleotide polymorphism rs5275. We then genotyped the rs5275 polymorphism in 183 affected and 223 unaffected individuals from our CRC predisposed families. Tests for association in the presence of linkage were made using family-based association tests. The C allele was found to be significantly associated (P<0.01) with diagnosis of hereditary non-syndromic CRC (P=0.0094, dominant model) and an earlier age of diagnosis (P=0.0089, heterozygous-advantage model). Interestingly, by stratifying the age of diagnosis data, we observed a speculative gender-discordant effect. Relative to other groups, female CC carriers were diagnosed less when young, but by 60 years of age were the most at risk group. Conversely, CT carriers of both genders showed a consistently earlier diagnosis relative to TT carriers. Our results suggest potential differential age-and gender-dependent efficacies of chemopreventative COX-2 inhibitors in the context of non-syndromic colorectal cancer.European Journal of Human Genetics advance online publication, 27 March 2013; doi:10.1038/ejhg.2013.53.

PMID: 23531863 [PubMed - as supplied by publisher]

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Increased levels of urinary PGE-M, a biomarker of inflammation, occur in association with obesity, aging and lung metastases in patients with breast cancer.

Increased levels of urinary PGE-M, a biomarker of inflammation, occur in association with obesity, aging and lung metastases in patients with breast cancer.

Cancer Prev Res (Phila). 2013 Mar 26;

Authors: Morris PG, Zhou XK, Milne GL, Goldstein D, Hawks L, Dang CT, Modi S, Fornier MN, Hudis CA, Dannenberg AJ

Abstract
Elevated levels of cyclooxygenase (COX)-derived prostaglandin E2 (PGE2) occur in inflamed tissues. To evaluate the potential links between inflammation and breast cancer, levels of urinary prostaglandin E-metabolite (PGE-M), a stable end metabolite of PGE2, were quantified. We enrolled 400 patients with breast cancer: controls with early breast cancer (n=200), lung metastases (n=100) and metastases to other sites (n=100). Patients completed a questionnaire, provided urine and had measurements of height and weight. Urinary PGE-M was quantified by mass spectrometry. Ever smokers with lung metastasis who had not been exposed to NSAIDs had the highest PGE-M levels. PGE-M levels were increased in association with elevated BMI (p<0.001), aging (p<0.001), pack-year smoking history (p=0.02), lung metastases (p=0.02) and recent cytotoxic chemotherapy (p=0.03). Conversely, use of NSAIDs, prototypic inhibitors of COX activity, was associated with reduced PGE-M levels (p<0.001). Based on the current findings, PGE-M is likely to be a useful biomarker for the selection of high risk subgroups to determine the utility of interventions that aim to reduce inflammation and possibly the development and progression of breast cancer, especially in overweight and obese women.

PMID: 23531446 [PubMed - as supplied by publisher]

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Effects of immunosuppression on alpha and beta cell renewal in transplanted mouse islets.

Effects of immunosuppression on alpha and beta cell renewal in transplanted mouse islets.

Diabetologia. 2013 Mar 27;

Authors: Krautz C, Wolk S, Steffen A, Knoch KP, Ceglarek U, Thiery J, Bornstein S, Saeger HD, Solimena M, Kersting S

Abstract
AIMS/HYPOTHESIS: Immunosuppressive drugs used in human islet transplantation interfere with the balance between beta cell renewal and death, and thus may contribute to progressive graft dysfunction. We analysed the influence of immunosuppressants on the proliferation of transplanted alpha and beta cells after syngeneic islet transplantation in streptozotocin-induced diabetic mice. METHODS: C57BL/6 diabetic mice were transplanted with syngeneic islets in the liver and simultaneously abdominally implanted with a mini-osmotic pump delivering BrdU alone or together with an immunosuppressant (tacrolimus, sirolimus, everolimus or mycophenolate mofetil [MMF]). Glycaemic control was assessed for 4�weeks. The area and proliferation of transplanted alpha and beta cells were subsequently quantified. RESULTS: After 4�weeks, glycaemia was significantly higher in treated mice than in controls. Insulinaemia was significantly lower in mice treated with everolimus, tacrolimus and sirolimus. MMF was the only immunosuppressant that did not significantly reduce beta cell area or proliferation, albeit its levels were in a lower range than those used in clinical settings. CONCLUSIONS/INTERPRETATION: After transplantation in diabetic mice, syngeneic beta cells have a strong capacity for self-renewal. In contrast to other immunosuppressants, MMF neither impaired beta cell proliferation nor adversely affected the fractional beta cell area. Although human beta cells are less prone to proliferate compared with rodent beta cells, the use of MMF may improve the long-term outcome of islet transplantation.

PMID: 23532258 [PubMed - as supplied by publisher]

c-met inhibitors zm-447439 rad001

Design, Synthesis, and Evaluation of New Tripeptides as COX-2 Inhibitors.

Design, Synthesis, and Evaluation of New Tripeptides as COX-2 Inhibitors.

J Amino Acids. 2013;2013:606282

Authors: Vernieri E, Gomez-Monterrey I, Milite C, Grieco P, Musella S, Bertamino A, Scognamiglio I, Alcaro S, Artese A, Ortuso F, Novellino E, Sala M, Campiglia P

Abstract
Cyclooxygenase (COX) is a key enzyme in the biosynthetic pathway leading to the formation of prostaglandins, which are mediators of inflammation. It exists mainly in two isoforms COX-1 and COX-2. The conventional nonsteroidal anti-inflammatory drugs (NSAIDs) have gastrointestinal side effects because they inhibit both isoforms. Recent data demonstrate that the overexpression of these enzymes, and in particular of cyclooxygenases-2, promotes multiple events involved in tumorigenesis; in addition, numerous studies show that the inhibition of cyclooxygenases-2 can delay or prevent certain forms of cancer. Agents that inhibit COX-2 while sparing COX-1 represent a new attractive therapeutic development and offer a new perspective for a further use of COX-2 inhibitors. The present study extends the evaluation of the COX activity to all 20(3) possible natural tripeptide sequences following a rational approach consisting in molecular modeling, synthesis, and biological tests. Based on data obtained from virtual screening, only those peptides with better profile of affinity have been selected and classified into two groups called S and E. Our results suggest that these novel compounds may have potential as structural templates for the design and subsequent development of the new selective COX-2 inhibitors drugs.

PMID: 23533709 [PubMed - in process]

c-met inhibitors zm-447439 rad001

Chronic treatment with baicalin prevents the chronic mild stress-induced depressive-like behavior: involving the inhibition of cyclooxygenase-2 in rat brain.

Chronic treatment with baicalin prevents the chronic mild stress-induced depressive-like behavior: involving the inhibition of cyclooxygenase-2 in rat brain.

Prog Neuropsychopharmacol Biol Psychiatry. 2013 Jan 10;40:138-43

Authors: Li YC, Shen JD, Li J, Wang R, Jiao S, Yi LT

Abstract
Baicalin, a major constituent of flavonoids isolated from Scutellariae Radix, has been previously confirmed to decrease the duration of immobility in mice exposed to the forced swimming test (FST) and tail suspension test (TST). However, its antidepressant effects and mechanisms are still seldom studied in chronic mild stress (CMS) model of depression. In the present study, we attempted to investigate the effects of baicalin on the depressive-like behavior, the mRNA expression and activity of cyclooxygenase-2 (COX-2), as well as prostaglandin E(2) (PGE(2)) levels in the frontal cortex and hippocampus. Moreover, the serum corticosterone levels were also examined. We found that CMS procedure not only decreased the sucrose preference and increased serum corticosterone levels, but also elevated the activity and mRNA expression of COX-2, and increased PGE(2) levels in rat brain regions. Treatment with baicalin (10, 20, 40 mg/kg) prevented these abnormalities induced by CMS. These results confirmed that baicalin exerted antidepressant-like effects, and suggested its mechanisms at least partially related to decease COX-2 activity and expression, subsequently resulted in reduction of PGE(2) levels in brain. Our findings may provide a new aspect to understand the antidepressant action of baicalin, which is targeted on the COX-2 system in brain.

PMID: 23022674 [PubMed - indexed for MEDLINE]

dovitinib dna-pk coxinhibitors

2013年3月27日星期三

Molecular design, synthesis and biological evaluation of cyclic imides bearing benzenesulfonamide fragment as potential COX-2 inhibitors. Part 2.

Molecular design, synthesis and biological evaluation of cyclic imides bearing benzenesulfonamide fragment as potential COX-2 inhibitors. Part 2.

Bioorg Med Chem Lett. 2013 Mar 7;

Authors: Al-Suwaidan IA, Alanazi AM, El-Azab AS, Al-Obaid AM, Eltahir KE, Maarouf AR, Abu El-Enin MA, Abdel-Aziz AA

Abstract
A group of cyclic imides (1-10) was designed for evaluation as a selective COX-2 inhibitors and investigated in vivo for their anti-inflammatory activity. Compounds 6a, 6b, 8a, 8b, 9a, 9b, 10a and 10b were proved to be potent COX-2 inhibitors with IC50 range of 0.1-4.0?M. In vitro COX-1/COX-2 inhibition structure-activity studies identified compound 8a as a highly potent (IC50=0.1?M), and an extremely selective [COX-2 (SI)>1000] comparable to celecoxib [COX-2 (SI)>384], COX-2 inhibitor that showed superior anti-inflammatory activity (ED50=72.4mg/kg) relative to diclofenac (ED50=114mg/kg). Molecular modeling was carried out through docking the designed compounds into the COX-2 binding site to predict if these compounds have analogous binding mode to the COX-2 inhibitors. The study showed that the homosulfonamide fragment of 8a inserted deep inside the 2�-pocket of the COX-2 active site, where the SO2NH2 group underwent H-bonding interaction with Gln(192)(2.95�), Phe(518)(2.82�) and Arg(513)(2.63 and 2.73�). Docking study of the synthesized compound 8a into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.

PMID: 23528298 [PubMed - as supplied by publisher]

dovitinib dna-pk coxinhibitors

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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Baicalein (5,6,7-trihydroxyflavone) reduces oxidative stress-induced DNA damage by upregulating the DNA repair system.

Baicalein (5,6,7-trihydroxyflavone) reduces oxidative stress-induced DNA damage by upregulating the DNA repair system.

Cell Biol Toxicol. 2012 Dec;28(6):421-33

Authors: Kim KC, Lee IK, Kang KA, Kim HS, Kang SS, Hyun JW

Abstract
Oxidative stress caused by reactive oxygen species (ROS) induces DNA base modifications and DNA strand breaks. In this study, the protective effect of baicalein against H(2)O(2)-induced DNA damage was investigated in V79-4 Chinese hamster fibroblast cells. H(2)O(2) treatment increased the levels of intracellular ROS and DNA double-strand breaks (DSBs) and decreased the level of Ku70 protein and the phosphorylation (activation) of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which are involved in the repair of DSBs by nonhomologous end joining. Baicalein effectively scavenged intracellular ROS induced by H(2)O(2), reduced DSBs, and rescued Ku70 protein level and phosphorylation of DNA-PKcs. In cellular response to DNA base damage, 8-oxoguanine DNA glycosylase 1 (OGG1) plays a vital role in the removal of 8-oxoguanine (8-OxoG), which is formed mainly by oxidative stress. Baicalein significantly decreased the levels of 8-OxoG induced by H(2)O(2), and this correlated with increases in OGG1 promoter activity and OGG1 mRNA and protein expression. The phosphorylated form of Akt kinase, which is a regulator of OGG1, was sharply decreased by H(2)O(2), but was prevented by baicalein. A specific Akt inhibitor abolished the cytoprotective effects of baicalein, suggesting that OGG1 induction by baicalein involves the Akt pathway. In conclusion, baicalein exerted protective effects against DNA damage induced by oxidative stress by activating DNA repair systems and scavenging ROS.

PMID: 23011636 [PubMed - indexed for MEDLINE]

zm-447439 rad001 ecdysone

A therapeutic approach to treat cardiovascular dysfunction of diabetes.

A therapeutic approach to treat cardiovascular dysfunction of diabetes.

Exp Toxicol Pathol. 2012 Nov;64(7-8):847-53

Authors: Bhatt LK, Veeranjaneyulu A

Abstract
Diabetes greatly increases risk of cardiovascular dysfunction and interruptions of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) have been shown to reduce the risk by alteration in extracellular matrix. We hypothesized that minocycline induced MMP-2 and MMP-9 inhibition can be enhanced by aspirin (through its COX and tPA inhibitory action) and this combination can reduce cardiovascular dysfunction of diabetes. Four weeks after diabetes induction (streptozotocin, 55 mg/kg, i.p.), rats were treated with minocycline (50 mg/kg, p.o.), aspirin (50 mg/kg, p.o.), or minocycline (50 mg/kg, p.o.) plus aspirin (50 mg/kg, p.o.) for a period of next four weeks. At the end of eighth week arterial pressure, heart rate and left ventricular pressure were recorded. Contractile response to phenylephrine (10(-5) M) and relaxation responses to acetylcholine (10(-9)-10(-4) M) were obtained from aortic rings of diabetic rats. Gel zymography was performed to evaluate MMP-2 and MMP-9 levels. Heart rate, mean arterial pressure, dp/dt(max) and dp/dt(min) were found significantly decreased in STZ diabetic rats when compared with normoglycemic group. Treatment with combination of minocycline and aspirin significantly ameliorate these compared to vehicle treated diabetic group. Endothelium-dependent relaxation responses induced by acetylcholine were decreased in diabetic rats and significantly higher in combination treated group. Collagen, MMP-2 and MMP-9 levels were significantly decreased in combined treated group when compared with diabetic control. Present study revealed that aspirin potentate minocycline induced MMP-2 and MMP-9 inhibition to ameliorate cardiovascular dysfunction of diabetes and this combination can be an approach for the treatment.

PMID: 21474293 [PubMed - indexed for MEDLINE]

c-met inhibitors zm-447439 rad001

Forging a link between oncogenic signaling and immunosuppression in melanoma.

Forging a link between oncogenic signaling and immunosuppression in melanoma.

Oncoimmunology. 2013 Feb 1;2(2):e22745

Authors: Khalili JS, Hwu P, Liz�e G

Abstract
Immunosuppressive tumor microenvironments limit the efficacy of T cell-based immunotherapy. We have recently demonstrated that the inhibition of BRAF(V600E) with vemurafenib relieves interleukin-1 (IL-1)-induced T-cell suppression as mediated by melanoma tumor associated fibroblasts (TAFs). These results suggest that inhibitors of the MAPK pathway in combination with T cell-based immunotherapies may induce long-lasting and durable responses.

PMID: 23525189 [PubMed - as supplied by publisher]

rad001 ecdysone chir-258

2013年3月26日星期二

Amniotic fluid stem cells improve survival and enhance repair of damaged intestine in necrotising enterocolitis via a COX-2 dependent mechanism.

Amniotic fluid stem cells improve survival and enhance repair of damaged intestine in necrotising enterocolitis via a COX-2 dependent mechanism.

Gut. 2013 Mar 24;

Authors: Zani A, Cananzi M, Fascetti-Leon F, Lauriti G, Smith VV, Bollini S, Ghionzoli M, D'Arrigo A, Pozzobon M, Piccoli M, Hicks A, Wells J, Siow B, Sebire NJ, Bishop C, Leon A, Atala A, Lythgoe MF, Pierro A, Eaton S, De Coppi P

Abstract
OBJECTIVE: Necrotising enterocolitis (NEC) remains one of the primary causes of morbidity and mortality in neonates and alternative strategies are needed. Stem cells have become a therapeutic option for other intestinal diseases, which share some features with NEC. We tested the hypothesis that amniotic fluid stem (AFS) cells exerted a beneficial effect in a neonatal rat model of NEC. DESIGN: Rats intraperitoneally injected with AFS cells and their controls (bone marrow mesenchymal stem cells, myoblast) were analysed for survival, behaviour, bowel imaging (MRI scan), histology, bowel absorption and motility, immunofluorescence for AFS cell detection, degree of gut inflammation (myeloperoxidase and malondialdehyde), and enterocyte apoptosis and proliferation. RESULTS: AFS cells integrated in the bowel wall and improved rat survival and clinical conditions, decreased NEC incidence and macroscopic gut damage, improved intestinal function, decreased bowel inflammation, increased enterocyte proliferation and reduced apoptosis. The beneficial effect was achieved via modulation of stromal cells expressing cyclooxygenase 2 in the lamina propria, as shown by survival studies using selective and non-selective cyclooxygenase 2 inhibitors. Interestingly, AFS cells differentially expressed genes of the Wnt/?-catenin pathway, which regulate intestinal epithelial stem cell function and cell migration and growth factors known to maintain gut epithelial integrity and reduce mucosal injury. CONCLUSIONS: We demonstrated here for the first time that AFS cells injected in an established model of NEC improve survival, clinical status, gut structure and function. Understanding the mechanism of this effect may help us to develop new cellular or pharmacological therapies for infants with NEC.

PMID: 23525603 [PubMed - as supplied by publisher]

ecdysone chir-258 dovitinib

Modulation of lymphangiogenesis: a new target for aspirin and other nonsteroidal anti-inflammatory agents? A systematic review.

Modulation of lymphangiogenesis: a new target for aspirin and other nonsteroidal anti-inflammatory agents? A systematic review.

J Clin Pharmacol. 2012 Nov;52(11):1749-54

Authors: Yiannakopoulou E

Abstract
Recent studies have implicated that lymphangiogenesis plays a role in the development of metastasis in experimental cancer models and in certain types of human tumors. Epidemiological and laboratory data suggest that non steroidal anti-inflammatory agents (NSAIDs) have antitumor activities, although the mechanisms have not been elucidated. This systematic review aimed to synthesize data on the effect of aspirin and other NSAIDs on lymphangiogenesis. In particular, an answer was attempted to be found for the following primary questions: Is there an effect of aspirin and NSAIDs on lymphangiogenesis? If yes, is this effect mediated through COX-II inhibition or through COX-II-independent mechanisms? Electronical databases were searched with the appropriate search terms for the period from 1966 up to and including February 2011. The few identified experimental trials indicated that aspirin and other NSAIDs inhibit lymphangiogenesis, with a potential decrease in metastatic spread, possibly through COX-II-dependent regulation of VEGF-C expression. COX-II-independent mechanisms of inhibition of lymphangiogenesis by salicylates and the other NSAIDs have not been investigated. Although further research validation is needed, this proposed effect of NSAIDs might have therapeutic implications in chemoprevention, adjuvant chemotherapy, and treatment of metastatic disease.

PMID: 22174438 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

Nuclear receptors HR96 and Ultraspiracle from the fall armyworm (Spodoptera frugiperda), developmental expression and induction by xenobiotics.

Nuclear receptors HR96 and Ultraspiracle from the fall armyworm (Spodoptera frugiperda), developmental expression and induction by xenobiotics.

J Insect Physiol. 2013 Mar 19;

Authors: Giraudo M, Audant P, Feyereisen R, Goff GL

Abstract
The fall armyworm Spodoptera frugiperda is a major polyphagous pest in agriculture and little is known on how this insect can adapt to the diverse and potentially toxic plant allelochemicals that they ingest or to insecticides. To investigate the involvement of nuclear receptors in the response of Spodoptera frugiperda to its chemical environment, we cloned SfHR96, a nuclear receptor orthologous to the mammalian xenobiotic receptors, pregnane X receptor (PXR) and constitutive androstane receptor (CAR). We also cloned Ultraspiracle (USP), the ortholog of retinoid X receptor (RXR) that serves as partner of dimerization of PXR and CAR. Cloning of SfUSP revealed the presence of two isoforms, SfUSP-1 and SfUSP-2 in this species, that differ in their N-terminal region. The expression of these receptors as well as the ecdysone receptor was studied during specific steps of development in different tissues. SfHR96 was constitutively expressed in larval midgut, fat body and Malpighian tubules throughout the last two instars and pupal stage, as well as in Sf9 cells. EcR and SfUSP-2 showed peaks of expression before larval moults and during metamorphosis, whereas SfUSP-1 was mainly expressed in the pre-pupal stage. Receptor induction was followed after exposure of larvae or cells to eleven chemicals compounds. SfHR96 was not inducible by the tested compounds. EcR was significantly induced by the 20- hydroxyecdysone agonist, methoxyfenozide, and SfUSP showed an increase expression when exposed to the juvenile hormone analog, methoprene. The cloning of these nuclear receptors is a first step in the understanding of the important capacities of adaptation of this insect pest.

PMID: 23523827 [PubMed - as supplied by publisher]

rad001 ecdysone chir-258

Amniotic fluid stem cells improve survival and enhance repair of damaged intestine in necrotising enterocolitis via a COX-2 dependent mechanism.

Amniotic fluid stem cells improve survival and enhance repair of damaged intestine in necrotising enterocolitis via a COX-2 dependent mechanism.

Gut. 2013 Mar 24;

PMID: 23525603 [PubMed - as supplied by publisher]

coxinhibitors c-met inhibitors zm-447439

2013年3月25日星期一

Essential role of grim-led programmed cell death for the establishment of corazonin-producing peptidergic nervous system during embryogenesis and metamorphosis in Drosophila melanogaster.

Essential role of grim-led programmed cell death for the establishment of corazonin-producing peptidergic nervous system during embryogenesis and metamorphosis in Drosophila melanogaster.

Biol Open. 2013 Mar 15;2(3):283-94

Authors: Lee G, Sehgal R, Wang Z, Nair S, Kikuno K, Chen CH, Hay B, Park JH

Abstract
In Drosophila melanogaster, combinatorial activities of four death genes, head involution defective (hid), reaper (rpr), grim, and sickle (skl), have been known to play crucial roles in the developmentally regulated programmed cell death (PCD) of various tissues. However, different expression patterns of the death genes also suggest distinct functions played by each. During early metamorphosis, a great number of larval neurons unfit for adult life style are removed by PCD. Among them are eight pairs of corazonin-expressing larval peptidergic neurons in the ventral nerve cord (vCrz). To reveal death genes responsible for the PCD of vCrz neurons, we examined extant and recently available mutations as well as RNA interference that disrupt functions of single or multiple death genes. We found grim as a chief proapoptotic gene and skl and rpr as minor ones. The function of grim is also required for PCD of the mitotic sibling cells of the vCrz neuronal precursors (EW3-sib) during embryonic neurogenesis. An intergenic region between grim and rpr, which, it has been suggested, may enhance expression of three death genes in embryonic neuroblasts, appears to play a role for the vCrz PCD, but not for the EW3-sib cell death. The death of vCrz neurons and EW3-sib is triggered by ecdysone and the Notch signaling pathway, respectively, suggesting distinct regulatory mechanisms of grim expression in a cell- and developmental stage-specific manner.

PMID: 23519152 [PubMed - in process]

dovitinib dna-pk coxinhibitors

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]

chir-258 dovitinib dna-pk

Metabolic adaptation to chronic inhibition of mitochondrial protein synthesis in acute myeloid leukemia cells.

Metabolic adaptation to chronic inhibition of mitochondrial protein synthesis in acute myeloid leukemia cells.

PLoS One. 2013;8(3):e58367

Authors: Jhas B, Sriskanthadevan S, Skrtic M, Sukhai MA, Voisin V, Jitkova Y, Gronda M, Hurren R, Laister RC, Bader GD, Minden MD, Schimmer AD

Abstract
Recently, we demonstrated that the anti-bacterial agent tigecycline preferentially induces death in leukemia cells through the inhibition of mitochondrial protein synthesis. Here, we sought to understand mechanisms of resistance to tigecycline by establishing a leukemia cell line resistant to the drug. TEX leukemia cells were treated with increasing concentrations of tigecycline over 4 months and a population of cells resistant to tigecycline (RTEX+TIG) was selected. Compared to wild type cells, RTEX+TIG cells had undetectable levels of mitochondrially translated proteins Cox-1 and Cox-2, reduced oxygen consumption and increased rates of glycolysis. Moreover, RTEX+TIG cells were more sensitive to inhibitors of glycolysis and more resistant to hypoxia. By electron microscopy, RTEX+TIG cells had abnormally swollen mitochondria with irregular cristae structures. RNA sequencing demonstrated a significant over-representation of genes with binding sites for the HIF1?:HIF1? transcription factor complex in their promoters. Upregulation of HIF1? mRNA and protein in RTEX+TIG cells was confirmed by Q-RTPCR and immunoblotting. Strikingly, upon removal of tigecycline from RTEX+TIG cells, the cells re-established aerobic metabolism. Levels of Cox-1 and Cox-2, oxygen consumption, glycolysis, mitochondrial mass and mitochondrial membrane potential returned to wild type levels, but HIF1? remained elevated. However, upon re-treatment with tigecycline for 72 hours, the glycolytic phenotype was re-established. Thus, we have generated cells with a reversible metabolic phenotype by chronic treatment with an inhibitor of mitochondrial protein synthesis. These cells will provide insight into cellular adaptations used to cope with metabolic stress.

PMID: 23520503 [PubMed - in process]

dovitinib dna-pk coxinhibitors

Novel dual cyclooxygenase and lipoxygenase inhibitors targeting hyaluronan-CD44v6 pathway and inducing cytotoxicity in colon cancer cells.

Novel dual cyclooxygenase and lipoxygenase inhibitors targeting hyaluronan-CD44v6 pathway and inducing cytotoxicity in colon cancer cells.

Bioorg Med Chem. 2013 Feb 27;

Authors: Misra S, Ghatak S, Patil N, Dandawate P, Ambike V, Adsule S, Unni D, Venkateswara Swamy K, Padhye S

Abstract
Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) enzyme have been found to play a role in promoting growth in colon cancer cell lines. The di-tert-butyl phenol class of compounds has been found to inhibit both COX-2 and 5-LOX enzymes with proven effectiveness in arresting tumor growth. In the present study, the structural analogs of 2,6 di-tert-butyl-p-benzoquinone (BQ) appended with hydrazide side chain were found to inhibit COX-2 and 5-LOX enzymes at micromolar concentrations. Molecular docking of the compounds into COX-2 and 5-LOX protein cavities indicated strong binding interactions supporting the observed cytototoxicities. The signaling interaction between endogenous hyaluronan and CD44 has been shown to regulate COX-2 activities through ErbB2 receptor tyrosine kinase (RTK) activation. In the present studies it has been observed for the first time, that three of our COX/5-LOX dual inhibitors inhibit proliferation upon hydrazide substitution and prevent the activity of pro-angiogenic factors in HCA-7, HT-29, Apc10.1 cells as well as the hyaluronan synthase-2 (Has2) enzyme over-expressed in colon cancer cells, through inhibition of the hyaluronan/CD44v6 cell survival pathway. Since there is a substantial enhancement in the antiproliferative activities of these compounds upon hydrazide substitution, the present work opens up new opportunities for evolving novel active compounds of BQ series for inhibiting colon cancer.

PMID: 23517721 [PubMed - as supplied by publisher]

ecdysone chir-258 dovitinib

Inactivation of DNA-Dependent Protein Kinase Promotes Heat-Induced Apoptosis Independently of Heat-Shock Protein Induction in Human Cancer Cell Lines.

Inactivation of DNA-Dependent Protein Kinase Promotes Heat-Induced Apoptosis Independently of Heat-Shock Protein Induction in Human Cancer Cell Lines.

PLoS One. 2013;8(3):e58325

Authors: Okazawa S, Furusawa Y, Kariya A, Hassan MA, Arai M, Hayashi R, Tabuchi Y, Kondo T, Tobe K

Abstract
The inhibition of DNA damage response pathway seems to be an attractive strategy for cancer therapy. It was previously reported that in rodent cells exposed to heat stress, cell growth was promoted by the activity of DNA-dependent protein kinase (DNA-PK), an enzyme involved in DNA non-homologous end joining (NHEJ) required for double-strand break repair. The absence of a functioning DNA-PK was associated with down regulation of heat shock protein 70 (HSP70). The objective of this study is thus to investigate the role of DNA-PK inhibition in heat-induced apoptosis in human cell lines. The inhibitors of phosphorylation of the DNA-PK catalytic subunit (DNA-PKcs) at Ser2056, such as NU7026 and NU7441, were utilized. Furthermore, knock down of DNA-PKcs was carried out using small interfering RNA (siDNA-PKcs). For heat exposure, cells were placed in water bath at 44�C for 60 min. Apoptosis was evaluated after 24 h incubation flow cytometrically. Proteins were extracted after 24 h and analyzed for HSP70 and HSP40 expression by Western blotting. Total RNA was extracted 6 h after treatment and analyzed using a GeneChip� microarray system to identify and select the up-regulated genes (?1.5 fold). The results showed an enhancement in heat-induced apoptosis in absence of functioning DNA-PKcs. Interestingly, the expression levels of HSP70 and HSP40 were elevated in the absence of DNA-PKcs under heat stress. The results of genetic network analysis showed that HSPs and JUN genes were up-regulated independently of DNA-PKcs in exposed parent and knock out cells. In the presence of functioning DNA-PKcs, there was an observed up-regulation of anti-apoptotic genes, such as NR1D1, whereas in the absence of DNA-PKcs the pro-apoptotic genes, such as EGR2, were preferentially up-regulated. From these findings, we concluded that in human cells, the inactivation of DNA-PKcs can promote heat-induced apoptosis independently of heat-shock proteins.

PMID: 23505488 [PubMed - in process]

coxinhibitors c-met inhibitors zm-447439

2013年3月24日星期日

A new approach to reducing postsurgical cancer recurrence: perioperative targeting of catecholamines and prostaglandins.

A new approach to reducing postsurgical cancer recurrence: perioperative targeting of catecholamines and prostaglandins.

Clin Cancer Res. 2012 Sep 15;18(18):4895-902

Authors: Neeman E, Zmora O, Ben-Eliyahu S

Abstract
Surgery is a crucial intervention in most cancer patients, but the perioperative period is characterized by increased risks for future outbreak of preexisting micrometastases and the initiation of new metastases-the major cause of cancer-related death. Here we argue that the short perioperative period is disproportionately critical in determining long-term recurrence rates, discuss the various underlying risk factors that act synergistically during this period, and assert that this time frame presents an unexplored opportunity to reduce long-term cancer recurrence. We then address physiologic mechanisms that underlie these risk factors, focusing on excess perioperative release of catecholamines and prostaglandins, which were recently shown to be prominent in facilitating cancer recurrence through their direct impact on the malignant tissue and its microenvironment, and through suppressing antimetastatic immunity. The involvement of the immune system is further discussed in light of accumulating evidence in cancer patients, and given the recent identification of endogenously activated unique leukocyte populations which, if not suppressed, can destroy autologous "immune-resistant" tumor cells. We then review animal studies and human correlative findings, suggesting the efficacy of blocking catecholamines and/or prostaglandins perioperatively, limiting metastasis and increasing survival rates. Finally, we propose a specific perioperative pharmacologic intervention in cancer patients, based on simultaneous ?-adrenergic blockade and COX-2 inhibition, and discuss specific considerations for its application in clinical trials, including our approved protocol. In sum, we herein present the rationale for a new approach to reduce long-term cancer recurrence by using a relatively safe, brief, and inexpensive intervention during the perioperative period.

PMID: 22753587 [PubMed - indexed for MEDLINE]

chir-258 dovitinib dna-pk

Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells.

Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells.

Mol Cancer Ther. 2013 Feb 26;

Authors: Konecny GE, Kolarova T, O'Brien NA, Winterhoff B, Yang G, Qi J, Qi Z, Venkatesan N, Ayala R, Luo T, Finn RS, Kristof J, Galderisi C, Graus Porta D, Anderson L, Shi MM, Yovine A, Slamon DJ

Abstract
The recent identification of activating fibroblast growth factor receptor 2 (FGFR2) mutations in endometrial cancer (EC) has generated an opportunity for a novel target-based therapy. Here we explore the therapeutic potential of two FGFR inhibitors, the multi-kinase inhibitor dovitinib (TKI258) and the more selective FGFR inhibitor NVP-BGJ398 for the treatment of EC. We examined the effects of both inhibitors on tumor cell growth, FGFR2 signaling, cell cycle and apoptosis using a panel of 20 molecularly characterized human EC cell lines. Anchorage independent growth was studied using soft agar assays. In vivo studies were conducted using EC xenograft models. Cell lines with activating FGFR2 mutations (S252W, N550K) were more sensitive to dovitinib or NVP-BGJ398 when compared to their FGFR2 wild-type counterparts (p=0.073 and p=0.021, respectively). Both agents inhibited FGFR2 signaling, induced cell cycle arrest and significantly increased apoptosis in FGFR2 mutant lines. In vitro, dovitinib and NVP-BGJ398 were both potent at inhibiting cell growth of FGFR2 mutant EC cells but the activity of dovitinib was less restricted to FGFR2 mutant lines when compared to NVP-BGJ398. In vivo, dovitinib and NVP-BGJ398 significantly inhibited the growth of FGFR2 mutated EC xenograft models. In addition, dovitinib showed significant antitumor activity in FGFR2 wild-type EC xenograft models including complete tumor regressions in a long term in vivo study. Dovitinib and NVP-BGJ398 warrant further clinical evaluation in patients with FGFR2 mutated EC. Dovitinib may have antitumor activity in EC beyond FGFR2 mutated cases and may permit greater flexibility in patient selection.

PMID: 23443805 [PubMed - as supplied by publisher]

rad001 ecdysone chir-258

DNA nanotechnology: a future perspective.

DNA nanotechnology: a future perspective.

Nanoscale Res Lett. 2013;8(1):119

Authors: Zahid M, Kim B, Hussain R, Amin R, Park SH

Abstract
In addition to its genetic function, DNA is one of the most distinct and smart self-assembling nanomaterials. DNA nanotechnology exploits the predictable self-assembly of DNA oligonucleotides to design and assemble innovative and highly discrete nanostructures. Highly ordered DNA motifs are capable of providing an ultra-fine framework for the next generation of nanofabrications. The majority of these applications are based upon the complementarity of DNA base pairing: adenine with thymine, and guanine with cytosine. DNA provides an intelligent route for the creation of nanoarchitectures with programmable and predictable patterns. DNA strands twist along one helix for a number of bases before switching to the other helix by passing through a crossover junction. The association of two crossovers keeps the helices parallel and holds them tightly together, allowing the assembly of bigger structures. Because of the DNA molecule's unique and novel characteristics, it can easily be applied in a vast variety of multidisciplinary research areas like biomedicine, computer science, nano/optoelectronics, and bionanotechnology.

PMID: 23497147 [PubMed - in process]

zm-447439 rad001 ecdysone

c-Met inhibitor SU11274 enhances the response of the prostate cancer cell line DU145 to ionizing radiation.

c-Met inhibitor SU11274 enhances the response of the prostate cancer cell line DU145 to ionizing radiation.

Biochem Biophys Res Commun. 2012 Oct 26;427(3):659-65

Authors: Yu H, Li X, Sun S, Gao X, Zhou D

Abstract
Hormone-refractory prostate cancer shows substantial resistance to most conventional therapies including radiotherapy, constitutes a key impediment to curing patients with the disease. c-Met overexpression plays a key role in prostate cancer tumorigenesis and disease progression. Here, we demonstrate that c-Met inhibition by SU11274 could significantly suppress cell survival and proliferation as well as enhance the radiosensitivity of DU145 cells. The underlying mechanisms of the effects of SU11274 on DU145 cells may include the inhibition of c-Met signaling, depolarization of the mitochondrial membrane potential, impairment of DNA repair function, abrogation of cell cycle arrest, and enhancement of cell death. Our study is the first to show the effectiveness of combining c-Met inhibition with ionizing radiation to cure hormone-refractory prostate cancer.

PMID: 23026049 [PubMed - indexed for MEDLINE]

dovitinib dna-pk coxinhibitors

Essential role of grim-led programmed cell death for the establishment of corazonin-producing peptidergic nervous system during embryogenesis and metamorphosis in Drosophila melanogaster.

Essential role of grim-led programmed cell death for the establishment of corazonin-producing peptidergic nervous system during embryogenesis and metamorphosis in Drosophila melanogaster.

Biol Open. 2013 Mar 15;2(3):283-94

Authors: Lee G, Sehgal R, Wang Z, Nair S, Kikuno K, Chen CH, Hay B, Park JH

PMID: 23519152 [PubMed - in process]

dna-pk coxinhibitors c-met inhibitors

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