Browsing by Subject "Piperazines"

Now showing 1 - 9 of 9

Open Access
A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53.
(Sci Signal, 2013-05-07) Kurokawa, Manabu; Kim, Jiyeon; Geradts, Joseph; Matsuura, Kenkyo; Liu, Liu; Ran, Xu; Xia, Wenle; Ribar, Thomas J; Henao, Ricardo; Dewhirst, Mark W; Kim, Wun-Jae; Lucas, Joseph E; Wang, Shaomeng; Spector, Neil L; Kornbluth, Sally
In the intrinsic pathway of apoptosis, cell-damaging signals promote the release of cytochrome c from mitochondria, triggering activation of the Apaf-1 and caspase-9 apoptosome. The ubiquitin E3 ligase MDM2 decreases the stability of the proapoptotic factor p53. We show that it also coordinated apoptotic events in a p53-independent manner by ubiquitylating the apoptosome activator CAS and the ubiquitin E3 ligase HUWE1. HUWE1 ubiquitylates the antiapoptotic factor Mcl-1, and we found that HUWE1 also ubiquitylated PP5 (protein phosphatase 5), which indirectly inhibited apoptosome activation. Breast cancers that are positive for the tyrosine receptor kinase HER2 (human epidermal growth factor receptor 2) tend to be highly aggressive. In HER2-positive breast cancer cells treated with the HER2 tyrosine kinase inhibitor lapatinib, MDM2 was degraded and HUWE1 was stabilized. In contrast, in breast cancer cells that acquired resistance to lapatinib, the abundance of MDM2 was not decreased and HUWE1 was degraded, which inhibited apoptosis, regardless of p53 status. MDM2 inhibition overcame lapatinib resistance in cells with either wild-type or mutant p53 and in xenograft models. These findings demonstrate broader, p53-independent roles for MDM2 and HUWE1 in apoptosis and specifically suggest the potential for therapy directed against MDM2 to overcome lapatinib resistance.
Open Access
Early clopidogrel versus prasugrel use among contemporary STEMI and NSTEMI patients in the US: insights from the National Cardiovascular Data Registry.
(J Am Heart Assoc, 2014-04-14) Sherwood, Matthew W; Wiviott, Stephen D; Peng, S Andrew; Roe, Matthew T; Delemos, James; Peterson, Eric D; Wang, Tracy Y
BACKGROUND: P2Y12 antagonist therapy improves outcomes in acute myocardial infarction (MI) patients. Novel agents in this class are now available in the US. We studied the introduction of prasugrel into contemporary MI practice to understand the appropriateness of its use and assess for changes in antiplatelet management practices. METHODS AND RESULTS: Using ACTION Registry-GWTG (Get-with-the-Guidelines), we evaluated patterns of P2Y12 antagonist use within 24 hours of admission in 100 228 ST elevation myocardial infarction (STEMI) and 158 492 Non-ST elevation myocardial infarction (NSTEMI) patients at 548 hospitals between October 2009 and September 2012. Rates of early P2Y12 antagonist use were approximately 90% among STEMI and 57% among NSTEMI patients. From 2009 to 2012, prasugrel use increased significantly from 3% to 18% (5% to 30% in STEMI; 2% to 10% in NSTEMI; P for trend <0.001 for all). During the same period, we observed a decrease in use of early but not discharge P2Y12 antagonist among NSTEMI patients. Although contraindicated, 3.0% of patients with prior stroke received prasugrel. Prasugrel was used in 1.9% of patients ≥75 years and 4.5% of patients with weight <60 kg. In both STEMI and NSTEMI, prasugrel was most frequently used in patients at the lowest predicted risk for bleeding and mortality. Despite lack of supporting evidence, prasugrel was initiated before cardiac catheterization in 18% of NSTEMI patients. CONCLUSIONS: With prasugrel as an antiplatelet treatment option, contemporary practice shows low uptake of prasugrel and delays in P2Y12 antagonist initiation among NSTEMI patients. We also note concerning evidence of inappropriate use of prasugrel, and inadequate targeting of this more potent therapy to maximize the benefit/risk ratio.
Open Access
Engineering a BCR-ABL-activated caspase for the selective elimination of leukemic cells.
(Proc Natl Acad Sci U S A, 2013-02-05) Kurokawa, Manabu; Ito, Takahiro; Yang, Chih-Sheng; Zhao, Chen; Macintyre, Andrew N; Rizzieri, David A; Rathmell, Jeffrey C; Deininger, Michael W; Reya, Tannishtha; Kornbluth, Sally
Increased understanding of the precise molecular mechanisms involved in cell survival and cell death signaling pathways offers the promise of harnessing these molecules to eliminate cancer cells without damaging normal cells. Tyrosine kinase oncoproteins promote the genesis of leukemias through both increased cell proliferation and inhibition of apoptotic cell death. Although tyrosine kinase inhibitors, such as the BCR-ABL inhibitor imatinib, have demonstrated remarkable efficacy in the clinic, drug-resistant leukemias emerge in some patients because of either the acquisition of point mutations or amplification of the tyrosine kinase, resulting in a poor long-term prognosis. Here, we exploit the molecular mechanisms of caspase activation and tyrosine kinase/adaptor protein signaling to forge a unique approach for selectively killing leukemic cells through the forcible induction of apoptosis. We have engineered caspase variants that can directly be activated in response to BCR-ABL. Because we harness, rather than inhibit, the activity of leukemogenic kinases to kill transformed cells, this approach selectively eliminates leukemic cells regardless of drug-resistant mutations.
Open Access
Extended-release ranolazine: critical evaluation of its use in stable angina.
(Vasc Health Risk Manag, 2011) Truffa, Adriano Am; Newby, L Kristin; Melloni, Chiara
Coronary heart disease is the major cause of morbidity and mortality throughout the world, and is responsible for approximately one of every six deaths in the US. Angina pectoris is a clinical syndrome characterized by discomfort, typically in the chest, neck, chin, or left arm, induced by physical exertion, emotional stress, or cold, and relieved by rest or nitroglycerin. The main goals of treatment of stable angina pectoris are to improve quality of life by reducing the severity and/or frequency of symptoms, to increase functional capacity, and to improve prognosis. Ranolazine is a recently developed antianginal with unique methods of action. In this paper, we review the pharmacology of ranolazine, clinical trials supporting its approval for clinical use, and studies of its quality of life benefits. We conclude that ranolazine has been shown to be a reasonable and safe option for patients who have refractory ischemic symptoms despite the use of standard medications (for example, nitrates, beta-adrenergic receptor antagonists, and calcium channel antagonists) for treatment of anginal symptoms, and also provides a modestly improved quality of life.
Open Access
PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically.
(Nat Med, 2016-01) Dickey, Audrey S; Pineda, Victor V; Tsunemi, Taiji; Liu, Patrick P; Miranda, Helen C; Gilmore-Hall, Stephen K; Lomas, Nicole; Sampat, Kunal R; Buttgereit, Anne; Torres, Mark-Joseph Manalang; Flores, April L; Arreola, Martin; Arbez, Nicolas; Akimov, Sergey S; Gaasterland, Terry; Lazarowski, Eduardo R; Ross, Christopher A; Yeo, Gene W; Sopher, Bryce L; Magnuson, Gavin K; Pinkerton, Anthony B; Masliah, Eliezer; La Spada, Albert R
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, which encodes a polyglutamine tract in the HTT protein. We found that peroxisome proliferator-activated receptor delta (PPAR-δ) interacts with HTT and that mutant HTT represses PPAR-δ-mediated transactivation. Increased PPAR-δ transactivation ameliorated mitochondrial dysfunction and improved cell survival of neurons from mouse models of HD. Expression of dominant-negative PPAR-δ in the central nervous system of mice was sufficient to induce motor dysfunction, neurodegeneration, mitochondrial abnormalities and transcriptional alterations that recapitulated HD-like phenotypes. Expression of dominant-negative PPAR-δ specifically in the striatum of medium spiny neurons in mice yielded HD-like motor phenotypes, accompanied by striatal neuron loss. In mouse models of HD, pharmacologic activation of PPAR-δ using the agonist KD3010 improved motor function, reduced neurodegeneration and increased survival. PPAR-δ activation also reduced HTT-induced neurotoxicity in vitro and in medium spiny-like neurons generated from stem cells derived from individuals with HD, indicating that PPAR-δ activation may be beneficial in HD and related disorders.
Open Access
Role of ST2 in non-ST-elevation acute coronary syndrome in the MERLIN-TIMI 36 trial.
(Clinical chemistry, 2012-01) Kohli, Payal; Bonaca, Marc P; Kakkar, Rahul; Kudinova, Anastacia Y; Scirica, Benjamin M; Sabatine, Marc S; Murphy, Sabina A; Braunwald, Eugene; Lee, Richard T; Morrow, David A
Objective
We investigated the prognostic performance of ST2 with respect to cardiovascular death (CVD) and heart failure (HF) in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) in a large multinational trial.
Background
Myocytes that are subjected to mechanical stress secrete ST2, a soluble interleukin-1 receptor family member that is associated with HF after STE-ACS.
Methods
We measured ST2 with a high-sensitivity assay in all available baseline samples (N=4426) in patients enrolled in the Metabolic Efficiency With Ranolazine for Less Ischemia in the Non-ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36), a placebo-controlled trial of ranolazine in NSTE-ACS. All events, including cardiovascular death and new or worsening HF, were adjudicated by an independent events committee.
Results
Patients with ST2 concentrations in the top quartile (>35 μg/L) were more likely to be older and male and have diabetes and renal dysfunction. ST2 was only weakly correlated with troponin and B-type natriuretic peptide. High ST2 was associated with increased risk for CVD/HF at 30 days (6.6% vs 1.6%, P<0.0001) and 1 year (12.2% vs 5.2%, P<0.0001). The risk associated with ST2 was significant after adjustment for clinical covariates and biomarkers (adjusted hazard ratio CVD/HF 1.90, 95% CI 1.15-3.13 at 30 days, P=0.012; 1.51, 95% CI 1.15-1.98 at 1 year, P=0.003), with a significant integrated discrimination improvement (P<0.0001). No significant interaction was found between ST2 and ranolazine (Pinteraction=0.15).
Conclusions
ST2 correlates weakly with biomarkers of acute injury and hemodynamic stress but is strongly associated with the risk of HF after NSTE-ACS. This biomarker and related pathway merit further investigation as potential therapeutic targets for patients with ACS at risk for cardiac remodeling.
Open Access
Synergistic antitumor effects of 9.2.27-PE38KDEL and ABT-737 in primary and metastatic brain tumors.
(PloS one, 2019-01-09) Yu, Xin; Dobrikov, Mikhail; Keir, Stephen T; Gromeier, Matthias; Pastan, Ira H; Reisfeld, Ralph; Bigner, Darell D; Chandramohan, Vidyalakshmi
Standard treatment, unfortunately, yields a poor prognosis for patients with primary or metastatic cancers in the central nervous system, indicating a necessity for novel therapeutic agents. Immunotoxins (ITs) are a class of promising therapeutic candidates produced by fusing antibody fragments with toxin moieties. In this study, we investigated if inherent resistance to IT cytotoxicity can be overcome by rational combination with pro-apoptotic enhancers. Therefore, we combined ITs (9.2.27-PE38KDEL or Mel-14-PE38KDEL) targeting chondroitin sulfate proteoglycan 4 (CSPG4) with a panel of Bcl-2 family inhibitors (ABT-737, ABT-263, ABT-199 [Venetoclax], A-1155463, and S63845) against patient-derived glioblastoma, melanoma, and breast cancer cells/cell lines. In vitro cytotoxicity assays demonstrated that the addition of the ABT compounds, specifically ABT-737, sensitized the different tumors to IT treatment, and improved the IC50 values of 9.2.27-PE38KDEL up to >1,000-fold. Mechanistic studies using 9.2.27-PE38KDEL and ABT-737 revealed that increased levels of intracellular IT, processed (active) exotoxin, and PARP cleavage correlated with the enhanced sensitivity to the combination treatment. Furthermore, we confirmed the synergistic effect of 9.2.27-PE38KDEL and ABT-737 combination therapy in orthotopic GBM xenograft and cerebral melanoma metastasis models in nude mice. Our study defines strategies for overcoming IT resistance and enhancing specific antitumor cytotoxicity in primary and metastatic brain tumors.
Open Access
Treatment with Imatinib in NSCLC is associated with decrease of phosphorylated PDGFR-beta and VEGF expression, decrease in interstitial fluid pressure and improvement of oxygenation.
(Br J Cancer, 2006-10-23) Vlahovic, G; Rabbani, ZN; Herndon, JE; Dewhirst, MW; Vujaskovic, Z
Elevated intratumoral interstitial fluid pressure (IFP) and tumour hypoxia are independent predictive factors for poor survival and poor treatment response in cancer patients. However, the relationship between IFP and tumour hypoxia has not yet been clearly established. Preclinical studies have shown that lowering IFP improves treatment response to cytotoxic therapy. Interstitial fluid pressure can be reduced by inhibition of phosphorylated platelet-derived growth factor receptor-beta (p-PDGFR-beta), a tyrosine kinase receptor frequently overexpressed in cancer stroma, and/or by inhibition of VEGF, a growth factor commonly overexpressed in tumours overexpressing p-PDGFR-beta. We hypothesised that Imatinib, a specific PDGFR-beta inhibitor will, in addition to p-PDGFR-beta inhibition, downregulate VEGF, decrease IFP and improve tumour oxygenation. A549 human lung adenocarcinoma xenografts overexpressing PDGFR-beta were grown in nude mice. Tumour-bearing animals were randomised to control and treatment groups (Imatinib 50 mg kg(-1) via gavage for 4 days). Interstitial fluid pressure was measured in both groups before and after treatment. EF5, a hypoxia marker, was administered 3 h before being killed. Tumours were sectioned and stained for p-PDGFR-beta, VEGF and EF5 binding. Stained sections were viewed with a fluorescence microscope and image analysis was performed. Imatinib treatment resulted in significant reduction of p-PDGFR-beta, VEGF and IFP. Tumour oxygenation was also significantly improved. This study shows that p-PDGFR-beta-overexpressing tumours can be effectively treated with Imatinib to decrease tumour IFP. Importantly, this is the first study demonstrating that Imatinib treatment improves tumour oxygenation and downregulates tumour VEGF expression.
Open Access
Use of PER977 to reverse the anticoagulant effect of edoxaban.
(N Engl J Med, 2014-11-27) Ansell, Jack E; Bakhru, Sasha H; Laulicht, Bryan E; Steiner, Solomon S; Grosso, Michael; Brown, Karen; Dishy, Victor; Noveck, Robert J; Costin, James C

Browsing by Subject "Piperazines"

Results Per Page

Sort Options

Objective

Background

Methods

Results

Conclusions