5-alpha-reductase

Ticagrelor versus clopidogrel in elderly patients with acute coronary syndromes: a substudy from the prospective randomized PLATelet inhibition and patient Outcomes (PLATO) trial.

Ticagrelor versus clopidogrel in elderly patients with acute coronary syndromes: a substudy from the prospective randomized PLATelet inhibition and patient Outcomes (PLATO) trial.

Circ Cardiovasc Qual Outcomes. 2012 Sep 1;5(5):680-8

Authors: Husted S, James S, Becker RC, Horrow J, Katus H, Storey RF, Cannon CP, Heras M, Lopes RD, Morais J, Mahaffey KW, Bach RG, Wojdyla D, Wallentin L, PLATO study group

Abstract
BACKGROUND: Elderly patients with acute coronary syndrome are at high risk of recurrent ischemic events and death, and for both antithrombotic therapy and catheter-based complications. This prespecified analysis investigates the effect and treatment-related complications of ticagrelor versus clopidogrel in elderly patients (?75 years of age) with acute coronary syndrome compared with those <75 years of age.
METHODS AND RESULTS: The association between age and the primary composite outcome, as well as major bleeding were evaluated in the PLATelet inhibition and patient Outcomes (PLATO) trial using Cox proportional hazards. Similar models were used to evaluate the interaction of age with treatment effects. Hazard ratios were adjusted for baseline characteristics. The clinical benefit of ticagrelor over clopidogrel was not significantly different between patients aged ?75 years of age (n=2878) and those <75 years of age (n=15 744) with respect to the composite of cardiovascular death, myocardial infarction, or stroke (interaction P=0.56), myocardial infarction (P=0.33), cardiovascular death (P=0.47), definite stent thrombosis (P=0.81), or all-cause mortality (P=0.76). No increase in PLATO-defined overall major bleeding with ticagrelor versus clopidogrel was observed in patients aged ?75 years (hazard ratio, 1.02; 95% confidence interval, 0.82-1.27) or patients aged <75 years (hazard ratio, 1.04; 95% confidence interval, 0.94-1.15). Dyspnea and ventricular pauses were more common during ticagrelor than clopidogrel treatment, with no evidence of an age-by-treatment interaction.
CONCLUSIONS: The significant clinical benefit and overall safety of ticagrelor compared with clopidogrel in acute coronary syndrome patients in the PLATO cohort were not found to depend on age.

PMID: 22991347 [PubMed - indexed for MEDLINE]

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]

Amelioration of cisplatin-induced rat renal lesions by a cyclooxygenase (COX)-2 selective inhibitor.

Amelioration of cisplatin-induced rat renal lesions by a cyclooxygenase (COX)-2 selective inhibitor.

Exp Toxicol Pathol. 2012 Sep;64(6):625-31

Authors: Yamamato E, Izawa T, Sawamoto O, Juniantito V, Kuwamura M, Yamate J

Abstract
Cyclooxygenase (COX)-2, an inducible form of COX, plays important roles in inflammatory lesions. We investigated effects of a COX-2 selective inhibitor, NS-398, on cisplatin (CDDP)-induced rat renal lesions. As compared with rats injected with a single dose of CDDP (6 mg/kg; CDDP group), rats who were treated everyday with NS-398 (3mg/kg) after the CDDP injection (inhibitor group), showed the declines of blood urea nitrogen and creatinine values, and the delay of the peak of regenerating renal epithelial cell number (demonstrable with 5'-bromo-2'-deoxyuridine immunohistochemistry); these findings suggested cytoprotective effects of the inhibitor. Furthermore, the numbers of ED1-immunopositive macrophages and ?-smooth muscle actin (?-SMA)-immunopositive myofibroblasts were lower in the inhibitor group than in the CDDP group; mRNA expression of transforming growth factor-?1 (TGF-?1) was also decreased in the inhibitor group. Because the fibrotic area seen after CDDP injection were tended to decrease in the inhibitor group compared with the CDDP group, it was considered that the decreased number of infiltrating macrophages by the inhibitor might lead to the decreased production of TGF-?1, thereby resulting in the reduced number of ?-SMA-positive myofibroblasts responsible for fibrosis. Collectively, although these differences between the CDDP and inhibitor groups were not always marked, the COX-2 inhibitor used in this study could ameliorate the CDDP-induced rat renal lesions.

PMID: 21256724 [PubMed - indexed for MEDLINE]

Mediterranean diet polyphenols reduce inflammatory angiogenesis through MMP-9 and COX-2 inhibition in human vascular endothelial cells: a potentially protective mechanism in atherosclerotic vascular disease and cancer.

Mediterranean diet polyphenols reduce inflammatory angiogenesis through MMP-9 and COX-2 inhibition in human vascular endothelial cells: a potentially protective mechanism in atherosclerotic vascular disease and cancer.

Arch Biochem Biophys. 2012 Nov 15;527(2):81-9

Authors: Scoditti E, Calabriso N, Massaro M, Pellegrino M, Storelli C, Martines G, De Caterina R, Carluccio MA

Abstract
Diets with high content of antioxidant polyphenols are associated with low prevalence of cardiovascular diseases and cancer. Inflammatory angiogenesis is a key pathogenic process both in cancer and atherosclerosis, and is tightly regulated by the proinflammatory enzyme cyclooxygenase (COX)-2 and the matrix degrading enzymes matrix metalloproteinases (MMPs). We studied the effects of antioxidant polyphenols from virgin olive oil (oleuropein and hydroxytyrosol) and red wine (resveratrol and quercetin) on endothelial cell angiogenic response in vitro, and explored underlying mechanisms. Cultured endothelial cells were pre-incubated with 0.1-50 ?mol/L polyphenols before stimulation with phorbol myristate acetate (PMA). All tested polyphenols reduced endothelial cell tube formation on matrigel and migration in wound healing assays. The reduced angiogenesis was associated with the inhibition of PMA-induced COX-2 protein expression and prostanoid production, as well as MMP-9 protein release and gelatinolytic activity. These effects were accompanied by a significant reduction in the stimulated intracellular reactive oxygen species levels and in the activation of the redox-sensitive transcription factor nuclear factor (NF)-?B. Our findings reveal that olive oil and red wine polyphenols reduce inflammatory angiogenesis in cultured endothelial cells, through MMP-9 and COX-2 inhibition, supporting a potential protective role for dietary polyphenols in atherosclerotic vascular disease and cancer.

PMID: 22595400 [PubMed - indexed for MEDLINE]

2012年12月14日星期五

UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil.

UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil.

World J Gastroenterol. 2012 Dec 7;18(45):6635-44

Authors: Wang Y, Shen L, Xu N, Wang JW, Jiao SC, Liu ZY, Xu JM

Abstract
AIM: To evaluate effects of UDP-glucuronosyltransferase1A1 (UGT1A1) and thymidylate synthetase (TS) gene polymorphisms on irinotecan in metastatic colorectal cancer (mCRC).
METHODS: Two irinotecan- and fluorouracil-based regimens, FOLFIRI and IFL, were selected as second-line therapy for 138 Chinese mCRC patients. Genomic DNA was extracted from peripheral blood samples before treatment. UGT1A1 and TS gene polymorphisms were determined by direct sequencing and restriction fragment length polymorphism, respectively. Gene polymorphisms of UGT1A1*28, UGT1A1*6 and promoter enhancer region of TS were analyzed. The relationship between genetic polymorphisms and clinical outcome, that is, response, toxicity and survival were assessed. Pharmacokinetic analyses were performed in a subgroup patients based on different UGT1A1 genotypes. Plasma concentration of irinotecan and its active metabolite SN-38 and inactive metabolite SN-38G were determined by high performance liquid chromatography. Differences in irinotecan and its metabolites between UGT1A1 gene variants were compared.
RESULTS: One hundred and eight patients received the FOLFIRI regimen, 29 the IFL regimen, and one irinotecan monotherapy. One hundred and thirty patients were eligible for toxicity and 111 for efficacy evaluation. One hundred and thirty-six patients were tested for UGT1A1*28 and *6 genotypes and 125 for promoter enhancer region of TS. Patients showed a higher frequency of wild-type UGT1A1*28 (TA6/6) compared with a Caucasian population (69.9% vs 45.2%). No significant difference was found between response rates and UGT1A1 genotype, although wild-type showed lower response rates compared with other variants (17.9% vs 24.2% for UGT1A1*28, 15.7% vs 26.8% for UGT1A1*6). When TS was considered, the subgroup with homozygous UGT1A1*28 (TA7/7) and non-3RG genotypes showed the highest response rate (33.3%), while wild-type UGT1A1*28 (TA6/6) with non-3RG only had a 13.6% response rate, but no significant difference was found. Logistic regression showed treatment duration was closely linked to clinical response. In toxicity comparison, UGT1A1*28 TA6/6 was associated with lower incidence of grade 2-4 diarrhea (27.8% vs 100%), and significantly reduced the risk of grade 4 neutropenia compared with TA7/7 (7.8% vs 37.5%). Wild-type UGT1A1*6 (G/G) tended to have a lower incidence of grade 3/4 diarrhea vs homozygous mutant (A/A) genotype (13.0% vs 40.0%). Taking UGT1A1 and TS genotypes together, lower incidence of grade 2-4 diarrhea was found in patients with non-3RG TS genotypes, when TA6/6 was compared with TA7/7 (35.3% vs 100.0%). No significant association with time to progression (TTP) and overall survival (OS) was observed with either UGT1A1 or TS gene polymorphisms, although slightly longer TTP and OS were found with UGT1A1*28 (TA6/6). Irinotecan PK was investigated in 34 patients, which showed high area under concentration curve (AUC) of irinotecan and SN-38, but low AUC ratio (SN-38G / SN-38) in those patients with UGT1A1*28 TA7/7.
CONCLUSION: A distinct distribution pattern of UGT1A1 genotypes in Chinese patients might contribute to relatively low toxicity associated with irinotecan and 5-fluorouracil in mCRC patients.

PMID: 23236239 [PubMed - in process]

Angiotensin II activates the calcineurin/NFAT signaling pathway and induces cyclooxygenase-2 expression in rat endometrial stromal cells.

Angiotensin II activates the calcineurin/NFAT signaling pathway and induces cyclooxygenase-2 expression in rat endometrial stromal cells.

PLoS One. 2012;7(5):e37750

Authors: Abraham F, Sacerdoti F, De Le�n R, Gentile T, Canellada A

Abstract
Cyclooxygenase (COX)-2, the inducible isoform of cyclooxygenase, plays a role in the process of uterine decidualization and blastocyst attachment. On the other hand, overexpression of COX-2 is involved in the proliferation of the endometrial tissue during endometriosis. Deregulation of the renin-angiotensin-system plays a role in the pathophysiology of endometriosis and pre-eclampsia. Angiotensin II increases intracellular Ca(2+) concentration by targeting phospholypase C-gamma in endometrial stromal cells (ESC). A key element of the cellular response to Ca(2+) signals is the activity of the Ca(2+)- and calmodulin-dependent phosphatase calcineurin. Our first aim was to study whether angiotensin II stimulated Cox-2 gene expression in rat ESC and to analyze whether calcineurin activity was involved. In cells isolated from non-pregnant uteri, COX-2 expression--both mRNA and protein--was induced by co-stimulation with phorbol ester and calcium ionophore (PIo), as well as by angiotensin II. Pretreatment with the calcineurin inhibitor cyclosporin A inhibited this induction. We further analyzed the role of the calcineurin/NFAT signaling pathway in the induction of Cox-2 gene expression in non-pregnant rat ESC. Cyclosporin A abolished NFATc1 dephosphorylation and translocation to the nucleus. Cyclosporin A also inhibited the transcriptional activity driven by the Cox-2 promoter. Exogenous expression of the peptide VIVIT -specific inhibitor of calcineurin/NFAT binding- blocked the activation of Cox-2 promoter and the up-regulation of COX-2 protein in these cells. Finally we analyzed Cox-2 gene expression in ESC of early-pregnant rats. COX-2 expression--both mRNA and protein--was induced by stimulation with PIo as well as by angiotensin II. This induction appears to be calcineurin independent, since it was not abrogated by cyclosporin A. In conclusion, angiotensin II induced Cox-2 gene expression by activating the calcineurin/NFAT signaling pathway in endometrial stromal cells of non-pregnant but not of early-pregnant rats. These results might be related to differential roles that COX-2 plays in the endometrium.

PMID: 22662209 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

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]

Malvidin-3-glucoside protects endothelial cells up-regulating endothelial NO synthase and inhibiting peroxynitrite-induced NF-kB activation.

Malvidin-3-glucoside protects endothelial cells up-regulating endothelial NO synthase and inhibiting peroxynitrite-induced NF-kB activation.

Chem Biol Interact. 2012 Sep 30;199(3):192-200

Authors: Paix�o J, Dinis TC, Almeida LM

Abstract
Anthocyanins are the most abundant flavonoid constituents of fruits and vegetables and several epidemiological studies suggest that the consumption of these compounds protect against several diseases, including vascular disorders. Previously, we have reported that anthocyanins are able to counteract peroxynitrite-induced apoptotic effects in endothelial cells through inhibition of several crucial signaling cascades, upstream and downstream of mitochondria. Following these studies, here we investigated possible effects of malvidin-3-glucoside, one of the main dietary anthocyanins, on NO bioavailability and on peroxynitrite-induced NF-kB activation in the same cell model. Our results show that treatment of bovine arterial endothelial cells with malvidin-3-glucoside up-regulated eNOS mRNA, leading to the enhancement of eNOS activity and NO production, an effect even greater when cells were further stimulated with peroxynitrite. On the other hand, in these activated endothelial cells, malvidin-3-glucoside suppressed pro-inflammatory mediators, namely iNOS expression/NO biosynthesis, COX-2 expression and IL-6 production, through inhibition of NF-kB activation. These findings suggest a potential role of malvidin-3-glucoside in NO balance and in inhibition of pro-inflammatory signaling pathways, supporting its benefits in cardiovascular health and pointing to anthocyanins as a promising tool for development of functional foods and nutraceuticals to improve endothelial function.

PMID: 22959858 [PubMed - indexed for MEDLINE]

NSAIDs: eNdocannabinoid stimulating anti-inflammatory drugs?

NSAIDs: eNdocannabinoid stimulating anti-inflammatory drugs?

Trends Pharmacol Sci. 2012 Sep;33(9):468-73

Authors: Fowler CJ

Abstract
Read any pharmacology textbook and the message is clear: nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibiting the activity of cyclooxygenase (COX) and thereby the production of prostaglandins. However, evidence is accumulating that NSAIDs involve the endocannabinoid system in their actions, and that such effects may pave the way towards the design of new analgesics that are not plagued with the gastrointestinal and cardiovascular adverse actions that are associated with this class of drugs. In this Opinion article, our current understanding of the involvement of the endocannabinoid system in the actions of NSAIDs is described, and the ways in which this can lead to novel drug development is discussed.

PMID: 22664342 [PubMed - indexed for MEDLINE]

2012年12月13日星期四

Association of clinical events with everolimus exposure in kidney transplant patients receiving reduced cyclosporine.

Association of clinical events with everolimus exposure in kidney transplant patients receiving reduced cyclosporine.

Clin Transplant. 2012 Dec 12;

Authors: Shihab FS, Cibrik D, Chan L, Kim YS, Carmellini M, Walker R, Zibari G, Pattison J, Cornu-Artis C, Wang Z, Tedesco-Silva Jr H

Abstract
BACKGROUND: The association between clinical events and everolimus exposure in patients receiving reduced-exposure calcineurin inhibitor therapy is poorly explored. METHODS: In a pre-planned, descriptive analysis of data from a randomized controlled trial, events were correlated with everolimus trough concentrations in 556 newly transplanted kidney transplant patients receiving everolimus with reduced-exposure cyclosporine (CsA) and steroids. Influence of everolimus exposure on clinical events was stratified according to predefined time-normalized concentrations. RESULTS: The incidence of treated biopsy-proven acute rejection and graft loss at month 12 was highest in patients with everolimus <3�ng/mL (36.4% and 28.6%, respectively, vs. 9.1-15.3% and 0.9-5.0% with higher concentration ranges). A higher mortality rate was observed in patients with an everolimus trough concentration ?12�ng/mL (10.0% vs. 1.7-5.6% with lower concentration ranges). The lowest rates of renal dysfunction (defined as poor renal function [estimated GFR, serum creatinine] or proteinuria), wound healing events, peripheral edema, new-onset diabetes mellitus, hypercholesterolemia and hypertriglyceridemia were generally observed with everolimus trough concentration in the range 3-8�ng/mL and CsA <100�ng/mL. Proteinuria occurred most frequently in patients with very low or very high everolimus trough concentrations. CONCLUSIONS: These results support an exposure-response relationship between clinical events and everolimus trough concentrations in kidney transplant patients receiving reduced-exposure CsA.

PMID: 23230975 [PubMed - as supplied by publisher]

Use of rivastigmine or galantamine and risk of adverse cardiac events: a database study from the Netherlands.

Use of rivastigmine or galantamine and risk of adverse cardiac events: a database study from the Netherlands.

Am J Geriatr Pharmacother. 2012 Dec;10(6):373-80

Authors: Kr�ger E, Berkers M, Carmichael PH, Souverein P, van Marum R, Egberts T

Abstract
BACKGROUND: Two cholinesterase inhibitors (ChEIs), rivastigmine and galantamine, are used to treat Alzheimer disease in the Netherlands. Several adverse cardiac events have been reported for these medications.
OBJECTIVE: We aimed to assess if the use of ChEIs increased the risk of cardiac events in the Netherlands.
METHODS: A cohort crossover study of the PHARMO Record Linking System database included patients who initiated ChEIs at age 50 years or older, had at least 1 dispensing of a ChEI drug between 1998 and 2008, a 1-year history in PHARMO, and 1 subsequent dispensing of any medication. Two outcomes were assessed: a first hospitalization for syncope or atrioventricular block. Poisson and Cox regression were used to calculate incidence densities and hazard ratios for cardiac events during periods with ChEI use, compared with periods without ChEI use.
RESULTS: During the complete observation period of 8.9 years (interquartile range 6.7 to 10.2) there were 132 first hospitalizations for atrioventricular block and 17 first hospitalizations for syncope among 3358 patients. The adjusted incidence densities were significantly increased during ChEI exposure for syncope and atrioventricular block, when compared with the background incidence densities in the roughly 5 years before the last year before ChEI initiation. However, when exposed periods were compared with the unexposed periods 1 year before ChEI initiation and times after exposure, the adjusted hazard ratios remained increased for syncope and atrioventricular block, but increases were not significant anymore.
CONCLUSIONS: Exposure to ChEIs might increase the risk of adverse cardiac events, but small numbers of cases limit conclusions about the risk in this population and research on larger study samples is needed.

PMID: 23217530 [PubMed - in process]

coxinhibitors c-met inhibitors zm-447439

Fragment-based discovery of novel and selective mPGES-1 inhibitors Part 1: Identification of sulfonamido-1,2,3-triazole-4,5-dicarboxylic acid.

Fragment-based discovery of novel and selective mPGES-1 inhibitors Part 1: Identification of sulfonamido-1,2,3-triazole-4,5-dicarboxylic acid.

Bioorg Med Chem Lett. 2012 Nov 15;

Authors: Lee K, Pham VC, Choi MJ, Kim KJ, Lee KT, Han SG, Yu YG, Lee JY

Abstract
Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible prostaglandin E synthase that catalyzes the conversion of prostaglandin PGH(2) to PGE(2) and represents a novel target for therapeutic treatment of inflammatory disorders. It is essential to identify mPGES-1 inhibitor with novel scaffold as new hit or lead compound for the purpose of the next-generation anti-inflammatory drugs. Herein we report the discovery of sulfonamido-1,2,3-triazole-4,5-dicarboxylic derivatives as a novel class of mPGES-1 inhibitors identified through fragment-based virtual screening and in vitro assays on the inhibitory activity of the actual compounds. 1-[2-(N-Phenylbenzenesulfonamido)ethyl]-1H-1,2,3-triazole-4,5-dicarboxylic acid (6f) inhibits human mPGES-1 (IC(50) of 1.1?M) with high selectivity (ca.1000-fold) over both COX-1 and COX-2 in a cell-free assay. In addition, the activity of compound 6f was again tested at 10?M concentration in presence of 0.1% Triton X-100 and found to be reduced to 1/4 of its original activity without this detergent. Compared to the complete loss of activity of nuisance inhibitor with the detergent, therefore, compound 6f would be regarded as a partial nuisance inhibitor of mPGES-1 with a novel scaffold for the optimal design of more potent mPGES-1 inhibitors.

PMID: 23218602 [PubMed - as supplied by publisher]

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

Use of rivastigmine or galantamine and risk of adverse cardiac events: a database study from the Netherlands.

Use of rivastigmine or galantamine and risk of adverse cardiac events: a database study from the Netherlands.

Am J Geriatr Pharmacother. 2012 Dec;10(6):373-80

Authors: Kr�ger E, Berkers M, Carmichael PH, Souverein P, van Marum R, Egberts T

PMID: 23217530 [PubMed - in process]

2012年12月12日星期三

The role of chemoprevention by selective cyclooxygenase-2 inhibitors in colorectal cancer patients - a population-based study.

The role of chemoprevention by selective cyclooxygenase-2 inhibitors in colorectal cancer patients - a population-based study.

BMC Cancer. 2012 Dec 6;12(1):582

Authors: Yang YH, Yang YH, Cheng CL, Ho PS, Ko YC

Abstract
ABSTRACT: BACKGROUND: There are limited population-based studies focusing on the chemopreventive effects of selective cyclooxygenase-2 (COX-2) inhibitors against colorectal cancer. The purpose of this study is to assess the trends and dose--response effects of various medication possession ratios (MPR) of selective COX-2 inhibitor used for chemoprevention of colorectal cancer. METHODS: A population-based case--control study was conducted using the Taiwan Health Insurance Research Database (NHIRD). The study comprised 21,460 colorectal cancer patients and 79,331 controls. The conditional logistic regression was applied to estimate the odds ratios (ORs) for COX-2 inhibitors used for several durations (5 years, 3 years, 1 year, 6 months and 3 months) prior to the index date. RESULTS: In patients receiving selective COX-2 inhibitors, the OR was 0.51 (95% CI=0.29~0.90, p=0.021) for an estimated 5-year period in developing colorectal cancer. ORs showing significant protection effects were found in 10% of MPRs for 5-year, 3-year, and 1-year usage. Risk reduction against colorectal cancer by selective COX-2 inhibitors was observed as early as 6 months after usage. CONCLUSION: Our results indicate that selective COX-2 inhibitors may reduce the development of colorectal cancer by at least 10% based on the MPRs evaluated. Given the limited number of clinical reports from general populations, our results add to the knowledge of chemopreventive effects of selective COX-2 inhibitors against cancer in individuals at no increased risk of colorectal cancer.

PMID: 23217168 [PubMed - as supplied by publisher]

Everolimus-Treated Renal Transplant Recipients Have a More Robust CMV-Specific CD8+ T-Cell Response Compared With Cyclosporine- or Mycophenolate-Treated Patients.

Everolimus-Treated Renal Transplant Recipients Have a More Robust CMV-Specific CD8+ T-Cell Response Compared With Cyclosporine- or Mycophenolate-Treated Patients.

Transplantation. 2012 Dec 4;

Authors: Havenith SH, Yong SL, van Donselaar-van der Pant KA, van Lier RA, Ten Berge IJ, Bemelman FJ

Abstract
BACKGROUND: In renal transplant recipients, mammalian target of rapamycin (mTOR) inhibitors have been reported to protect against cytomegalovirus (CMV) disease. Here, we questioned whether mTOR inhibitors specifically influence human CMV-induced T-cell responses. METHODS: We studied renal transplant recipients treated with prednisolone, cyclosporine A (CsA), and mycophenolate sodium (MPS) for the first 6 months after transplantation followed by double therapy consisting of prednisolone/everolimus, which is an mTOR inhibitor (P/EVL; n=10), prednisolone/CsA (P/CsA; n=7), or prednisolone/MPS (P/MPS; n=9). All patients were CMV-IgG positive before transplantation. CMV reactivation was detectable in the first 6 months after transplantation and not thereafter. None of the patients included in this study suffered from CMV disease. Both CD27CD8 and CD27CD28CD4 effector-type T-cell counts, known to be associated with CMV infection, were measured before transplantation and at 6 and 24 months after transplantation. Additionally, we determined both number and function of CMV-specific CD8 T cells at these time points. RESULTS: The number of total CD8 T cells, CD27CD8 T cells, and CD28CD4 T cells increased significantly after switch to therapy with P/EVL but not after switch to P/CsA or P/MPS. Specifically, CMV-specific CD8 T-cell counts significantly increased after switch to therapy with P/EVL. Furthermore, the mTOR inhibitor sirolimus strongly inhibited alloresponses in vitro, whereas it did not affect CMV-specific responses. CONCLUSION: We observed a significant increase in (CMV-specific) effector-type CD8 and CD4 T-cell counts in everolimus-treated patients. These findings may at least in part explain the reported low incidence of CMV-related pathology in everolimus-treated patients.

PMID: 23222818 [PubMed - as supplied by publisher]

Nadir CD4+, religion, antiretroviral therapy, incidence of type 2 diabetes mellitus, and increasing rates of obesity among black Africans with HIV disease.

Nadir CD4+, religion, antiretroviral therapy, incidence of type 2 diabetes mellitus, and increasing rates of obesity among black Africans with HIV disease.

Int J Gen Med. 2012;5:983-90

Authors: Mandina Ndona M, Longo-Mbenza B, Wumba R, Tandu Umba B, Buassa-Bu-Tsumbu B, Mbula Mambimbi M, Wobin TO, Mbungu Fuele S

Abstract
BACKGROUND: The purpose of this study was to determine the cross-sectional association between some sociodemographic factors and antiretroviral therapy (ART), as well as the incidence and predictors of type 2 diabetes mellitus among Central Africans with human immunodeficiency virus (HIV) disease.
METHODS: This study had a cross-sectional design and was a prospective analysis of 102 patients with HIV disease (49 on ART versus 53 not on ART) in Kinshasa, Democratic Republic of Congo, between 2004 and 2008. A Cox regression model was used to assess for any relationship between type 2 diabetes and exposure to combination ART without protease inhibitors, after adjusting for known risk factors for type 2 diabetes, nadir CD4 and CD8 levels, viral load, marital status, and religion.
RESULTS: Unexpectedly elevated rates of smoking, excess alcohol intake, and ART-related total, abdominal, and peripheral obesity were observed in our study group of HIV patients. At the end of follow-up, five patients were diagnosed with type 2 diabetes (incidence rate 4.9%, 9.8 per 1000 person-years). Univariate risk factors for type 2 diabetes were male gender (relative risk [RR] 1.1, 95% confidence interval [CI] 1.01-1.4; P = 0.019), traditional religion versus new charismatic religion (RR 1.1, 95% CI 1.01-1.3; P = 0.046), exposure to ART (RR 1.1, 95% CI 1.002-1.3; P = 0.034), and single status (RR 6.2, 95% CI 1.5-15; P = 0.047). In multivariate analysis, strong significant independent predictors of type 2 diabetes were belonging to a traditional religion (HR 2.1, 95% CI 1.1-4.2; P = 0.036) and a relative increase in nadir CD4 cell count (beta coefficient 0.003; P < 0.0001).
CONCLUSION: ART-related obesity and type 2 diabetes are becoming increasing problems in Central Africans with HIV disease. A relative increase in nadir CD4 count and traditional religion status appear to be the strongest independent predictors of type 2 diabetes.

PMID: 23226071 [PubMed - in process]

Two-year outcomes after deployment of XIENCE V everolimus-eluting stents in patients undergoing percutaneous coronary intervention of bifurcation lesions: A report from the SPIRIT V single Arm study.

Two-year outcomes after deployment of XIENCE V everolimus-eluting stents in patients undergoing percutaneous coronary intervention of bifurcation lesions: A report from the SPIRIT V single Arm study.

Catheter Cardiovasc Interv. 2012 Dec 7;

Authors: D?av�k V, Kaul U, Guagliumi G, Chevalier B, Smits PC, Stuteville M, Li D, Sudhir K, Grube E

Abstract
OBJECTIVES: The aim of this analysis was to analyze outcomes of patients undergoing Xience V EES treatment of bifurcation lesions, a subset in which treatment is particularly challenging. BACKGROUND: The SPIRIT V Study provided an evaluation of the Xience V everolimus eluting stent (EES) performance in complex patient and lesion population. METHODS: The SPIRIT V Single Arm Study enrolled 2700 patients with de-novo coronary artery lesions suitable to be optimally treated with a maximum of four planned Xience V EES. Lesion evaluation was by visual assessment. The outcomes of the 492 patients undergoing Xience V EES stenting of ?1 bifurcation lesion were compared to those with no bifurcation lesion treated. RESULTS: Compared to those without bifurcation treatment, patients with bifurcation treatment were more likely to have multi-vessel disease (49% vs 40%), left main treatment (3.1% vs 0.9%), more lesions treated (1.5 vs 1.3), calcification (36.4% vs 27.5%), and ostial (17.1% vs 8.2%) and angulated lesions (29.3% vs 21.1%), all p<0.001. The 30-day composite rate of death, myocardial infarction (MI), target vessel revascularization (TVR) was 4.3% in patients with bifurcation PCI and 2.2% in those with non-bifurcation PCI (p=0.017). At 2 years, this composite event rate was 11.3% and 10.0% in these two groups respectively (p=0.403). Rates of cardiac death, MI, target lesion revascularization (TLR), TVR, and ARC defined definite or probable stent thrombosis (0.4% vs 0.9%, p=0.402) were not significantly different between the two groups. CONCLUSIONS: Despite greater patient and lesion complexity, treatment of patients with bifurcation lesions using the Xience V EES in the SPIRIT V prospective Single Arm Study was safe and effective, with low overall event rates that were similar to those without bifurcation lesion treatment. � 2012 Wiley Periodicals, Inc.

PMID: 23225766 [PubMed - as supplied by publisher]

2012年12月11日星期二

A novel SND1-BRAF fusion confers resistance to c-Met inhibitor PF-04217903 in GTL16 cells though MAPK activation.

A novel SND1-BRAF fusion confers resistance to c-Met inhibitor PF-04217903 in GTL16 cells though MAPK activation.

PLoS One. 2012;7(6):e39653

Authors: Lee NV, Lira ME, Pavlicek A, Ye J, Buckman D, Bagrodia S, Srinivasa SP, Zhao Y, Aparicio S, Rejto PA, Christensen JG, Ching KA

Abstract
Targeting cancers with amplified or abnormally activated c-Met (hepatocyte growth factor receptor) may have therapeutic benefit based on nonclinical and emerging clinical findings. However, the eventual emergence of drug resistant tumors motivates the pre-emptive identification of potential mechanisms of clinical resistance. We rendered a MET amplified gastric cancer cell line, GTL16, resistant to c-Met inhibition with prolonged exposure to a c-Met inhibitor, PF-04217903 (METi). Characterization of surviving cells identified an amplified chromosomal rearrangement between 7q32 and 7q34 which overexpresses a constitutively active SND1-BRAF fusion protein. In the resistant clones, hyperactivation of the downstream MAPK pathway via SND1-BRAF conferred resistance to c-Met receptor tyrosine kinase inhibition. Combination treatment with METi and a RAF inhibitor, PF-04880594 (RAFi) inhibited ERK activation and circumvented resistance to either single agent. Alternatively, treatment with a MEK inhibitor, PD-0325901 (MEKi) alone effectively blocked ERK phosphorylation and inhibited cell growth. Our results suggest that combination of a c-Met tyrosine kinase inhibitor with a BRAF or a MEK inhibitor may be effective in treating resistant tumors that use activated BRAF to escape suppression of c-Met signaling.

PMID: 22745804 [PubMed - indexed for MEDLINE]

A positive-margin resection model recreates the postsurgical tumor microenvironment and is a reliable model for adjuvant therapy evaluation.

A positive-margin resection model recreates the postsurgical tumor microenvironment and is a reliable model for adjuvant therapy evaluation.

Cancer Biol Ther. 2012 Jul;13(9):745-55

Authors: Predina JD, Judy B, Fridlender ZG, Aliperti LA, Madajewski B, Kapoor V, Cheng G, Quatromoni J, Okusanya O, Singhal S

Abstract
Up to 30% of cancer patients undergoing curative surgery develop local recurrences due to positive margins. Patients typically receive adjuvant chemotherapy, immunotherapy and/or radiation to prevent such relapses. Interestingly, evidence supporting these therapies is traditionally derived in animal models of primary tumors, thus failing to consider surgically induced tumor microenvironment changes that may influence adjuvant therapy efficacy. To address this consideration, we characterized a murine model of local cancer recurrence. This model was reproducible and generated a postoperative inflammatory tumor microenvironment that resembles those observed following human cancer surgery. To further validate this model, antagonists of two pro-inflammatory mediators, TGF? and COX-2, were tested and found to be effective in decreasing the growth of recurrent tumors. We appreciated that preoperative TGF? inhibition led to wound dehiscence, while postoperative initiation of COX-2 inhibition resulted in a loss of efficacy. In summary, although not an exact replica of all human cancer surgeries, our proposed local recurrence approach provides a biologically relevant and reliable model useful for preclinical evaluation of novel adjuvant therapies. The use of this model yields results that may be overlooked using traditional preclinical cancer models that fail to incorporate a surgical component.

PMID: 22617772 [PubMed - in process]

Pharmacokinetics of intravenous and intramuscular parecoxib in healthy Beagles.

Pharmacokinetics of intravenous and intramuscular parecoxib in healthy Beagles.

Vet J. 2012 Jul;193(1):246-50

Authors: Giorgi M, Saccomanni G, Del Carlo S, Manera C, Lavy E

Abstract
Parecoxib is an inactive pro-drug that is rapidly converted to valdecoxib, a selective cyclooxygenase (COX)-2 inhibitor registered for the management of post-operative pain in humans. Recent studies have suggested that parecoxib has excellent clinical efficacy and safety in veterinary species. The aim of the current study was to assess the pharmacokinetics of parecoxib and valdecoxib after intravenous (i.v.) and intramuscular (i.m.) administration. Seven healthy male Beagle dogs received 2.5 mg/kg parecoxib by either the i.v. or i.m. route in a cross-over design, with the alternative route of administration used 1 week later. The plasma concentrations of both analytes were detected according to a previously validated method using high performance liquid chromatography with fluorescence detection (HPLC-FL). No adverse effects were observed in any animal during the study. For both routes of administration, parecoxib was rapidly and almost completely converted to valdecoxib. The parecoxib/valdecoxib area under the curve (AUC) ratio for both routes of administration was 1.4. The half-life of valdecoxib was about 2 h, which was shorter than reported for humans, although the plasma concentrations following both routes of administration were likely to be effective for analgesia. The absolute bioavailability of parecoxib was 66%. The pharmacokinetic features of parecoxib make it suitable for treatment of acute pain in the canine species.

PMID: 22130459 [PubMed - in process]

Contractile activity-induced mitochondrial biogenesis and mTORC1.

Contractile activity-induced mitochondrial biogenesis and mTORC1.

Am J Physiol Cell Physiol. 2012 Sep 1;303(5):C540-7

Authors: Carter HN, Hood DA

Abstract
In response to exercise training, or chronic contractile activity, mitochondrial content is known to be enriched within skeletal muscle. However, the molecular mechanisms that mediate this adaptation are incompletely defined. Recently, the protein complex, mammalian target of rapamycin complex 1 (mTORC1), has been identified to facilitate the expression of nuclear genes encoding mitochondrial proteins (NUGEMPs) in resting muscle cells via the interaction of the mTORC1 components, mTOR and raptor, the transcription factor Yin Yang 1, and peroxisome proliferator-activated receptor-? coactivator-1?. It is currently unknown if this mechanism is operative during the increase in mitochondrial content that occurs within skeletal muscle with chronic contractile activity (CCA). Thus we employed a cell culture model of murine skeletal muscle and subjected the myotubes to CCA for 3 h per day for 4 consecutive days in the presence or absence of the mTORC1 inhibitor rapamycin. CCA produced increases in the mitochondrial markers cytochrome oxidase (COX) IV (2.5-fold), Tfam (1.5-fold), and COX activity (1.6-fold). Rapamycin-mediated inhibition of mTORC1 did not suppress these CCA-induced increases in mitochondrial proteins and organelle content. mTORC1 inhibition alone produced a selective upregulation of mitochondrial proteins (COX IV, Tfam), but diminished organelle state 3 respiration. CCA restored this impairment to normal. Our results suggest that mTORC1 activity is not integral for the increase in mitochondrial content elicited by CCA, but is required to maintain mitochondrial function and homeostasis in resting muscle.

PMID: 22700793 [PubMed - in process]

2012年12月10日星期一

The natural alkaloid berberine targets multiple pathways to induce cell death in cultured human colon cancer cells.

The natural alkaloid berberine targets multiple pathways to induce cell death in cultured human colon cancer cells.

Eur J Pharmacol. 2012 Aug 5;688(1-3):14-21

Authors: Chidambara Murthy KN, Jayaprakasha GK, Patil BS

Abstract
In the current paper, berberine, an isoquinoline alkaloid, was tested for its chemopreventive potential in colon cancer (SW480) cells. Berberine inhibited proliferation of colon cancer cells in a dose- and time-dependent manner. Interestingly, this compound exhibited minimum toxicity in normal cells at 200 ?M. Berberine arrested SW480 cell cycle at G2/M phase, which was supported by induction of p21 expression. Induction of a series of biochemical events, including loss of mitochondrial membrane potential, release of cytochrome-c to cytosol, induction of Bcl-2 family proteins, caspases and cleavage of poly (ADP-ribose) polymerase (PARP), by berberine suggests its ability to induce apoptosis. In addition, berberine also inhibited inflammation, as evidenced by induction of expression of NF?B and Cox(2). Furthermore, berberine inhibited caspase-8 mediated angiogenesis, as confirmed through expression of tumor necrotic factor related apoptosis-inducing ligand (TRAIL), vascular endothelial growth factor (VEGF) and survivin. The results of the current study demonstrated that berberine has the ability to cause cell cycle arrest, induce apoptosis and inhibit inflammation in colon cancer cells. The magnitude of the effects observed suggests that berberine may be worth considering for further studies of its potential applications for improving health, either as a preventative or a potential treatment.

PMID: 22617025 [PubMed - in process]

ecdysone chir-258

The selective cyclooxygenase-2 inhibitor parecoxib markedly improves the ability of the duodenum to regulate luminal hypertonicity in anaesthetized rats.

The selective cyclooxygenase-2 inhibitor parecoxib markedly improves the ability of the duodenum to regulate luminal hypertonicity in anaesthetized rats.

Acta Physiol (Oxf). 2012 Jul;205(3):433-51

Authors: Sedin J, Sj�blom M, Nylander O

Abstract
AIM: To examine whether the prevention of post-operative duodenal ileus by treatment with parecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, affects the ability of the duodenum to respond to luminal hypertonicity.
METHODS: The proximal duodenums of anaesthetized rats were perfused with hypertonic NaCl solutions with osmolalities of 400, 500, 600 or 700 mOsm kg(-1) , and the effects on mucosal permeability, motility, transepithelial net fluid flux and effluent osmolality were assessed in the absence (control) and presence of parecoxib.
RESULTS: Parecoxib-treated, but not control animals, exhibited duodenal contractions, which were reduced by the nicotinic receptor antagonists mecamylamine and hexamethonium and by perfusion with 700 mOsm kg(-1) . All animals responded to luminal hypertonicity with induction of net fluid secretion, which peaked at an osmolality of 500 mOsm kg(-1) . The hypertonicity-induced increases in fluid secretion were twofold greater in parecoxib-treated than in control rats and attenuated by nicotinic receptor blockade. The decrease in luminal osmolality correlated with the osmolality of the perfusion solution in both control and parecoxib-treated animals but the osmolality-adjusting capability was markedly better in the latter group. Rats exposed to duodenal luminal distension responded to hypertonicity with a greater fluid secretion and a larger decrease in luminal osmolality than control rats. Perfusion with 700 mOsm kg(-1) increased mucosal permeability in parecoxib-treated animals only, an effect abolished by nicotinic receptor blockade.
CONCLUSION: Parecoxib markedly improved the ability of the duodenum to sense and to decrease luminal hypertonicity by a mechanism most probably involving inhibition of COX-2 and stimulation of nicotinic acetylcholine receptors.

PMID: 22251854 [PubMed - in process]

Repeated CMV infection in a heart transplantation patient.

Repeated CMV infection in a heart transplantation patient.

Case Rep Transplant. 2012;2012:305920

Authors: Melero-Ferrer J, Sanchez-Lazaro IJ, Navea-Tejerina A, Almenar-Bonet L, Blanes-Julia M, Martinez-Dolz L, Salvador-Sanz A

Abstract
Infections are one of the leading causes of morbidity and mortality in heart transplantation (HTx). Cytomegalovirus (CMV) is the most common viral infection during the first year after HTx, but it is more unusual after this time. We present the case of a patient who underwent an HTx due to a severe ischemic heart disease. Although the patient did not have a high risk for CMV, infection, he suffered a reactivation during the first year and then up to six more episodes, especially in his eyes. The patient received different treatments against CMV and the immunosuppression was changed several times. Finally, everolimus was introduced instead of cyclosporine, and mycophenolate mofetil was withdrawn. The presented case provides an example of how the immunosupresion plays a key role in some infections in spite of being a suitable antiviral treatment.

PMID: 23213610 [PubMed - in process]

Inhibition of survivin and aurora B kinase sensitizes mesothelioma cells by enhancing mitotic arrests.

Inhibition of survivin and aurora B kinase sensitizes mesothelioma cells by enhancing mitotic arrests.

Int J Radiat Oncol Biol Phys. 2007 Apr 1;67(5):1519-25

Authors: Kim KW, Mutter RW, Willey CD, Subhawong TK, Shinohara ET, Albert JM, Ling G, Cao C, Gi YJ, Lu B

Abstract
PURPOSE: Survivin, a member of the inhibitor of apoptosis gene family, has also been shown to regulate mitosis. It binds Aurora B kinase and the inner centromere protein to form the chromosome passenger complex. Both Aurora B and survivin are overexpressed in many tumors. In this study, we examined whether irradiation affected survivin and Aurora B expression in mesothelioma cells, and how inhibition of these molecules affected radiosensitivity.
METHODS AND MATERIALS: ZM447439 and survivin antisense oligonucleotides were used to inhibit survivin and Aurora B kinase respectively. Western blot was performed to determine the expression of survivin, Aurora B, phosphorylated-histone H3 (Ser 10), and caspase cleavage. Multinucleated cells were counted using flow cytometry, and cell survival after treatment was determined using clonogenic assay.
RESULTS: At 3-Gy irradiation an increase was observed in levels of survivin and Aurora B as well as the kinase activity of Aurora B, with an increase in G2/M phase. The radiation-induced upregulation of these molecules was effectively attenuated by antisense oligonucleotides against survivin and a small-molecule inhibitor of Aurora B, ZM447439. Dual inhibition of survivin and Aurora B synergistically radiosensitized mesothelioma cells with a dose enhancement ratio of 2.55. This treatment resulted in increased formation of multinucleated cells after irradiation but did not increase levels of cleaved caspase 3.
CONCLUSION: Inhibition of survivin and Aurora B induces mitotic cell arrest in mesothelioma cells after irradiation. These two proteins may be potential therapeutic targets for the enhancement of radiotherapy in malignant pleural mesothelioma.

PMID: 17394948 [PubMed - indexed for MEDLINE]

Cell cycle dependent degradation of MCAK: evidence against a role in anaphase chromosome movement.

Cell cycle dependent degradation of MCAK: evidence against a role in anaphase chromosome movement.

Cell Cycle. 2008 Oct;7(20):3187-93

Authors: Ganguly A, Bhattacharya R, Cabral F

Abstract
MCAK, a kinesin related motor protein with microtubule depolymerizing activity, is known to play an important role in spindle assembly and correcting errors in mitotic chromosome alignment. Experiments to determine how cellular levels of the protein are regulated demonstrate that MCAK accumulates during cell cycle progression, reaches a maximum at G(2)/M phase, and is rapidly degraded by the proteasome during mitosis. Immunofluorescence microscopy further indicates that MCAK largely disappears from kinetochores and spindle poles at the metaphase to anaphase transition. A phosphorylated form of MCAK appears during mitosis and seems to be preferentially degraded, but degradation does not appear to depend on Aurora B, a kinase reported to be involved in regulating the error correcting activity of the protein. These studies indicate that MCAK activity is limited during the latter stages of mitosis by protein degradation, and argue against a role for the protein in anaphase chromosome movement.

PMID: 18843200 [PubMed - indexed for MEDLINE]

2012年12月9日星期日

A novel treatment strategy targeting Aurora kinases in acute myelogenous leukemia.

A novel treatment strategy targeting Aurora kinases in acute myelogenous leukemia.

Mol Cancer Ther. 2007 Jun;6(6):1851-7

Authors: Ikezoe T, Yang J, Nishioka C, Tasaka T, Taniguchi A, Kuwayama Y, Komatsu N, Bandobashi K, Togitani K, Koeffler HP, Taguchi H

Abstract
The Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. Aberrant expression of these kinases occurs in solid tumors and is associated with aneuploidy and carcinogenesis. We found in this study that Aurora kinase A and B were aberrantly expressed in a variety of types of human leukemia cell lines (n = 15, e.g., PALL-1, PALL-2, HL-60, NB4, MV4-11, etc.), as well as freshly isolated leukemia cells from individuals with acute myelogenous leukemia (n = 44) compared with bone marrow mononuclear cells from healthy volunteers (n = 11), as measured by real-time PCR. ZM447439 is a novel selective Aurora kinase inhibitor. The compound induced growth inhibition, caused accumulation of cells with 4N/8N DNA content, and mediated apoptosis of human leukemia cells as measured by thymidine uptake, cell cycle analysis, and annexin V staining, respectively. Especially profound growth inhibition occurred with the PALL-1 and PALL-2 cells, which possess wild-type p53 gene. In contrast, ZM447439 did not inhibit clonogenic growth of myeloid committed stem cells harvested from healthy normal volunteers. Taken together, inhibition of Aurora kinases may be a promising treatment strategy for individuals with leukemia.

PMID: 17541033 [PubMed - indexed for MEDLINE]

Antiproliferative effect of Aurora kinase targeting in mesothelioma.

Antiproliferative effect of Aurora kinase targeting in mesothelioma.

Lung Cancer. 2010 Dec;70(3):271-9

Authors: Crispi S, Fagliarone C, Biroccio A, D'Angelo C, Galati R, Sacchi A, Vincenzi B, Baldi A, Verdina A

Abstract
The Aurora proteins are a small family of serine/threonine kinase that function in various stages of mitosis. Current interest in Aurora kinase relates to its role in tumours, and its potential as a therapeutic target. In this work we studied the expression of Aurora kinases A and B and related genes in human mesothelioma tissues and in five mesothelioma cell lines. Moreover, we analyzed the effects of ZM447439 (ZM), an Aurora kinase inhibitor, on cellular growth. Results evidenced an over-expression of Aurora kinase A and related genes in human mesothelioma tissues and an over-expression of Aurora kinases A and B in all cell lines. Moreover, we demonstrated that ZM447439 was able to inhibit cell growth in all cell lines and that this inhibition was due to a specific effect as demonstrated by the reduction in the level of Histone H3 phosphorylation. Our findings support a role of Aurora kinase in mesothelioma and the possibility of using Aurora kinase inhibitors in therapeutic modalities.

PMID: 20371132 [PubMed - indexed for MEDLINE]

Inhibition of Aurora kinases perturbs chromosome alignment and spindle checkpoint signaling in rat spermatocytes.

Inhibition of Aurora kinases perturbs chromosome alignment and spindle checkpoint signaling in rat spermatocytes.

Exp Cell Res. 2006 Nov 1;312(18):3459-70

Authors: Wang Y, Toppari J, Parvinen M, Kallio MJ

Abstract
In somatic cells, integrity of cell division is safeguarded by the spindle checkpoint, a signaling cascade that delays the separation of sister chromatids in the presence of misaligned chromosomes. Aurora kinases play important roles in this process by promoting centrosome maturation, chromosome bi-orientation, spindle checkpoint signaling, and cytokinesis. To investigate the functions of Aurora kinases in male meiosis, we applied a small molecule Aurora inhibitor, ZM447439, to seminiferous tubules in vitro. Primary and secondary spermatocytes exposed to ZM447439 exhibit defects in the spindle morphology and fail to align their chromosomes at the metaphase plate. Moreover, the treated spermatocytes undergo a forced exit from the meiotic M-phase without cytokinesis. These results suggest that the activities of Aurora kinases are required for normal spindle assembly as well as for establishment and maintenance of proper microtubule-kinetochore attachments and spindle checkpoint signaling in male mammalian meiosis.

PMID: 16962097 [PubMed - indexed for MEDLINE]

A novel treatment strategy targeting Aurora kinases in acute myelogenous leukemia.

A novel treatment strategy targeting Aurora kinases in acute myelogenous leukemia.

Mol Cancer Ther. 2007 Jun;6(6):1851-7

Authors: Ikezoe T, Yang J, Nishioka C, Tasaka T, Taniguchi A, Kuwayama Y, Komatsu N, Bandobashi K, Togitani K, Koeffler HP, Taguchi H

PMID: 17541033 [PubMed - indexed for MEDLINE]

Effects of the aurora kinase inhibitors AZD1152-HQPA and ZM447439 on growth arrest and polyploidy in acute myeloid leukemia cell lines and primary blasts.

Effects of the aurora kinase inhibitors AZD1152-HQPA and ZM447439 on growth arrest and polyploidy in acute myeloid leukemia cell lines and primary blasts.

Haematologica. 2008 May;93(5):662-9

Authors: Walsby E, Walsh V, Pepper C, Burnett A, Mills K

Abstract
BACKGROUND: Aurora kinases play an essential role in the orchestration of chromosome separation and cytokinesis during mitosis. Small-molecule inhibition of the aurora kinases has been shown to result in inhibition of cell division, phosphorylation of histone H3 and the induction of apoptosis in a number of cell systems. These characteristics have led aurora kinase inhibitors to be considered as potential therapeutic agents.
DESIGN AND METHODS: Aurora kinase gene expression profiles were assessed in 101 samples from patients with acute myeloid leukemia. Subsequently, aurora kinase inhibitors were investigated for their in vitro effects on cell viability, histone H3 phosphorylation, cell cycle and morphology in acute myeloid leukemia cell lines and primary acute myeloid leukemia samples.
RESULTS: The aurora kinase inhibitors AZD1152-HQPA and ZM447439 induced growth arrest and the accumulation of hyperploid cells in acute myeloid leukemia cell lines and primary acute myeloid leukemia cultures. Furthermore, both agents inhibited histone H3 phosphorylation and this preceded perturbations in cell cycle and the induction of apoptosis. Single cell cloning assays were performed on diploid and polyploid cells to investigate their colony-forming capacities. Although the polyploid cells showed a reduced capacity for colony formation when compared with their diploid counterparts, they were consistently able to form colonies.
CONCLUSIONS: AZD1152-HQPA- and ZM447439 are effective apoptosis-inducing agents in acute myeloid leukemia cell lines and primary acute myeloid leukemia cultures. However, their propensity to induce polyploidy does not inevitably result in apoptosis.

PMID: 18367484 [PubMed - indexed for MEDLINE]