Abstract：
:Telomerase activity is expressed in most types of cancer cells but not in normal somatic cells, suggesting that telomerase may be an important target for cancer chemotherapy. Inhibition of telomerase results in telomere erosion, leading to the subsequent growth arrest of cancer cells followed by senescence or cell death. In this study, we screened a chemical library for the inhibition of human telomerase, identifying three inhibitors. All compounds contained a common nitrostyrene moiety conjugated to different side chains. One of these compounds, 3-(3,5-dichlorophenoxy)-nitrostyrene (DPNS), showed the most potent inhibitory effect, with 50% inhibition at approximately 0.4 microM and did not inhibit DNA and RNA polymerases, including retroviral reverse transcriptase. A series of enzyme kinetic experiments suggests that DPNS is a mixed-type noncompetitive inhibitor, with an inhibitor-binding site distinct from the binding sites for the telomeric substrate primer and the deoxynucleoside-5'-triphosphates. Extensive propagation of cancer cell line in the presence of DPNS resulted in progressive telomere erosion followed by the induction of senescence phenotype. The results presented here demonstrate that DPNS is a highly selective, small-molecule telomerase inhibitor in vitro and could be useful as a lead molecule for the further development of inhibitors with an improved potential for efficacy in vivo.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Kim JH,Kim JH,Lee GE,Lee JE,Chung IKdoi
10.1124/mol.63.5.1117keywords:
subject
Has Abstractpub_date
2003-05-01 00:00:00pages
1117-24issue
5eissn
0026-895Xissn
1521-0111journal_volume
63pub_type
杂志文章abstract：:Systematic series of monoamines, diamines, and triamines were used to define the structural requirements for interaction at the polyamine recognition site of the N-methyl-D-aspartate receptor complex. Effects of amines on binding of [3H]MK-801 to washed synaptic plasma membranes were measured in the presence of L-glut...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1992-04-01 00:00:00
abstract：:The relationship between the phospholipase-stimulating and immunosuppressive properties of cyclosporin A (CsA) has been investigated in vitro. At concentrations of 0.025 microM and upwards, CsA caused dose-related inhibition of both mitogen- and alloantigen-stimulated uptake of tritiated thymidine by human mononuclear...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1993-09-01 00:00:00
abstract：:K201 (JTV-519) may prevent abnormal Ca(2+) leak from the sarcoplasmic reticulum (SR) in the ischemic heart and skeletal muscle (SkM) by stabilizing the ryanodine receptors (RyRs; RyR1 and RyR2, respectively). We tested direct modulation of the SR Ca(2+)-stimulated ATPase (SERCA) and RyRs by K201. In isolated cardiac a...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.115.102277
更新日期：2016-08-01 00:00:00
abstract：:Undesired block of human ERG1 potassium channels is the basis for cardiac side effects of many different types of drugs. Therefore, it is important to know exactly why some drugs particularly bind to these channels with high affinity. Upon expression in mammalian cells and Xenopus laevis oocytes, we investigated the i...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.65.5.1120
更新日期：2004-05-01 00:00:00
abstract：:Based on biochemical and ligand binding studies in various tissues and species, evidence for several alpha 2-adrenergic receptor subtypes has accumulated. The current alpha 2-adrenergic receptor classification (alpha 2A, alpha 2B, alpha 2C) is based exclusively on pharmacological criteria. The molecular cloning of thr...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1990-11-01 00:00:00
abstract：:Endothelin-1 (ET) and ATP mobilize Ca2+ in rat C6 glioma cells by stimulating phosphoinositide turnover. Both agents also inhibit adenylyl cyclase (AC) activity in C6 glioma cells. The goal of this study was to characterize the molecular mechanisms responsible for the inhibition of AC activity. The administration of e...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1993-07-01 00:00:00
abstract：:Recently we demonstrated that the effects of beta 2-adrenoceptor (AR) stimulation to augment Ca2+ current (ICa), cytosolic Ca2+ (Cai) transients, and contractility in rat ventricular myocytes are largely dissociated from its effect to increase cellular cAMP levels. This result suggested that beta 2ARs might be coupled...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1995-02-01 00:00:00
abstract：:Benzamide riboside (BR) and tiazofurin (TR) are converted to analogs of NAD that inhibit IMP dehydrogenase (IMPDH), resulting in cellular depletion of GTP and dGTP and inhibition of proliferation. The current work was undertaken to identify the human nucleoside transporters involved in cellular uptake of BR and TR and...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.104.004408
更新日期：2005-01-01 00:00:00
abstract：:Smooth muscle preparations of human aorta or pig coronary arteries contain nearly equal amounts of cGMP-dependent protein kinase isozymes (cGMP kinase I alpha and I beta). In order to understand the roles of these isozymes in relaxing vascular smooth muscle, several new cGMP analogs were synthesized and tested for pot...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1992-07-01 00:00:00
abstract：:Corticotropin-releasing factor (CRF) receptors encoded by two distinct genes have recently been identified and termed CRF1 and CRF2. CRF and the non-mammalian-related peptide sauvagine bind to and activate CRF1 receptors with high affinity and equal potency. Although CRF is significantly weaker at the CRF2 receptor, s...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1996-09-01 00:00:00
abstract：:Potassium channels play fundamental roles in physiology. Chemically diverse drugs bind in the pore region of K+ channels. Here, we homology-modeled voltage- and Ca2+-gated K+ channel BK and voltage-gated Kv1.3 using the X-ray structures of MthK and Kv1.2, respectively, and simulated the binding of d-tubocurarine in th...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.105.017970
更新日期：2006-04-01 00:00:00
abstract：:Aldehyde dehydrogenase-2 (ALDH2) catalyzes vascular bioactivation of the antianginal drug nitroglycerin (GTN) to yield nitric oxide (NO) or a related species that activates soluble guanylate cyclase (sGC), resulting in cGMP-mediated vasodilation. Accordingly, established ALDH2 inhibitors attenuate GTN-induced vasorela...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.113.086835
更新日期：2013-09-01 00:00:00
abstract：:We have recently demonstrated that the alpha 2-adrenergic radioligand [3H]idazoxan also labels additional sites that do not recognize catecholamines but bind with high affinity several chemically distinct drugs previously assumed to be highly selective for alpha 2-adrenergic receptors [Mol. Pharmacol. 35:324-330 (1989...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1990-01-01 00:00:00
abstract：:Obesity is now recognized as a rapidly increasing worldwide threat to health, largely as a result of causing diabetes. Thus, considerable efforts are underway in the pharmaceutical industry to find drugs to treat this condition. Target validation in various academic and industrial laboratories has revealed a number of...
journal_title：Molecular pharmacology
pub_type： 杂志文章,评审
doi：10.1124/mol.106.026104
更新日期：2006-09-01 00:00:00
abstract：:Prokaryotes produce a variety of toxins that affect genomic function of both eukaryotes and prokaryotes. The 375-base pair bacterial gene Streptoalloteichus hindustanus (Sh) ble encodes a small protein, Streptoalloteichus hindustanus bleomycin resistance protein (BRP), that inhibits in vitro DNA cleavage by the prokar...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1993-12-01 00:00:00
abstract：:In the rat isolated optic nerve, nitric oxide (NO) activates soluble guanylyl cyclase (sGC), resulting in a selective accumulation of cGMP in the axons. The axons are also selectively vulnerable to NO toxicity. The experiments initially aimed to determine any causative link between these two effects. It was shown, usi...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.61.1.97
更新日期：2002-01-01 00:00:00
abstract：:The toxicity of acetaminophen (4'-hydroxyacetanilide), 3,5-dimethylacetaminophen (3'-5'-dimethyl-4'-hydroxyacetanilide), and 2,6-dimethylacetaminophen (2',6'-dimethyl-4'-hydroxyacetanilide) was investigated in hepatocytes isolated from phenobarbital-pretreated rats. At a concentration of 5 mM, acetaminophen was found ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1987-06-01 00:00:00
abstract：:The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) play a major part in the control of drug metabolism and transport. We have previously shown that PXR and CAR expression is controlled by the glucocorticoid receptor (GR) and proposed the existence of a signal transmission cascade GR-(PXR/CAR)...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.105.022046
更新日期：2006-07-01 00:00:00
abstract：:Voltage-gated sodium channels (Navs) are promising targets for analgesic and antiepileptic therapies. Although specificity between Nav subtypes may be desirable to target specific neural types, such as nociceptors in pain, many broadly acting Nav inhibitors are clinically beneficial in neuropathic pain and epilepsy. H...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/molpharm.120.000079
更新日期：2021-01-01 00:00:00
abstract：:We have identified alpha 2-adrenergic receptors on human erythroleukemia (HEL) cells, a suspension-grown cell line related to human platelets. properties of receptors were assessed in intact cells by binding of the antagonist [3H]yohimbine and by inhibition of cAMP accumulation. [3H]Yohimbine labeled 5900 +/- 2100 rec...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1987-08-01 00:00:00
abstract：:UDP-glucuronosyltransferase (UGT) 1A1 glucuronidates endogenous metabolites, such as bilirubin, and exogenous substances, and plays a critical role in their detoxification and excretion. In a previous article, we described the phenobarbital response activity to a 290-base pair (bp) distal enhancer sequence (-3499/-321...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.104.007161
更新日期：2005-03-01 00:00:00
abstract：:Mutations that inhibit Kv11.1 ion channel activity contribute to abnormalities of cardiac repolarization that can lead to long QT2 (LQT2) cardiac arrhythmias and sudden death. However, for most of these mutations, nothing is known about the molecular mechanism linking Kv11.1 malfunction to cardiac death. We have previ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.112.077966
更新日期：2012-09-01 00:00:00
abstract：:The ligand specificity of rat adenohypophyseal vasopressin receptors was directly compared to that of peripheral receptors of the V1 and V2 types. For this purpose a series of 15 recently designed vasopressin antagonists was used. The affinities of these antagonists for rat adenohypophyseal membranes were deduced from...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1986-08-01 00:00:00
abstract：:Adenosine uptake via nucleoside transporters is inhibited when S49 and NG108-15 cell lines cells are exposed to ethanol. This inhibition leads to an accumulation of extracellular adenosine that binds to adenosine A2 receptors and increases cAMP production. Subsequently, there is a heterologous desensitization of recep...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1993-11-01 00:00:00
abstract：:Cytotoxic effects of quinones are thought to be mediated by redox cycles between quinones and quinols whereby reactive oxygen species are generated. The role of glucuronidation in preventing these toxic redox cycles was investigated by using benzo(a)pyrene-3,6-quinone and isolated rat hepatocytes or Reuber hepatoma ce...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1985-04-01 00:00:00
abstract：:Epoxyeicosatrienoic acids (EETs), products of the cytochrome P-450 monooxygenase metabolism of arachidonic acid, can regulate the activity of ion channels. We examined the effects of EETs on cardiac L-type Ca2+ channels that play important roles in regulating cardiac contractility, controlling heart rate, and mediatin...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.55.2.288
更新日期：1999-02-01 00:00:00
abstract：:Westernization of dietary habits increases lipid intake and is responsible for increased numbers of patients with atherosclerotic diseases. Niemann-Pick C1-Like 1 (NPC1L1)-a cholesterol importer-plays a crucial role in dietary cholesterol absorption in the intestine and is closely associated with several lipid-related...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.119.115840
更新日期：2019-07-01 00:00:00
abstract：:We describe the nucleic acid sequence encoding a human 5-hydroxytryptamine1D (5-HT1D) serotonin receptor and some of the functional characteristics of the gene product. The receptor gene was isolated by hybridization to a probe based on a canine thyroid cDNA (called RDC4) previously isolated by others and believed to ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1991-08-01 00:00:00
abstract：:1-Deoxynojirimycin (DNM) is a saccharide decoy that inhibits cellular alpha-glucosidase I-II activity. Treatment by DNM of human immunodeficiency virus (HIV)-infected lymphocyte cultures inhibits virus spread. The functional properties of the membrane-associated Env glycoprotein (Env) modified in the presence of DNM r...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.61.1.186
更新日期：2002-01-01 00:00:00
abstract：:Propofol, etomidate, and barbiturate anesthetics are allosteric coagonists at pentameric α1β3γ2 GABAA receptors, modulating channel activation via four biochemically established intersubunit transmembrane pockets. Etomidate selectively occupies the two β+/α- pockets, the barbiturate photolabel R-5-allyl-1-methyl-5-(m-...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.118.115048
更新日期：2019-04-01 00:00:00
