Abstract：
:The cytotoxic efficacy of antitumor drugs targeted at DNA topoisomerase II (topo II) in many cases varies in direct proportion to cellular topo II content. To investigate the transcriptional control of the predominant alpha form of topo II, the 5' flanking region of the human topo II alpha gene (positions -562 to +90) was subcloned into a firefly luciferase reporter plasmid and transiently transfected into HL-60 human leukemia cells, a line capable of monocytic differentiation after treatment with various agents. Early in phorbol-12-myristate-13-acetate (30 nM)-induced differentiation (18-24 hr after treatment), an unexpected 3-5-fold activation of topo II alpha gene promoter activity was observed. Activation was observed in HL-60 cells and U-937 cells, but not in HeLa human cervical carcinoma cells. Sodium butyrate (NaB) (0.4 mM) also led to activation (4-17-fold) of the topo II alpha promoter in HL-60 and U-937 cells. Promoter sequences between position -90 and position +90 mediated the inducing effects of NaB. This NaB-dependent promoter-reporter induction was partly mirrored by a transient approximately 2-fold increase in endogenous topo II alpha enzyme. The stimulus for promoter activation could be partly attributed to a 2-fold increase in DNA synthesis at 16 hr for NaB, but not phorbol-12-myristate-13-acetate. Regardless of the primary stimulus for topo II alpha promoter trans-activation, it could be bypassed by treatment of HL-60 cells with NaB for 48 hr before transfection, revealing the expected 60-70% suppression of topo II alpha promoter activity. Further study of topo II alpha promoter down-regulation later in monocytic differentiation may serve as a model for elucidating the transcriptional mechanisms that may also be exploited by tumor cells expressing intrinsic or acquired resistance to topo II-directed drugs.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Fraser DJ,Brandt TL,Kroll DJsubject
Has Abstractpub_date
1995-04-01 00:00:00pages
696-706issue
4eissn
0026-895Xissn
1521-0111journal_volume
47pub_type
杂志文章abstract：:Merbarone (5-[N-phenyl carboxamido]-2-thiobarbituric acid) is an anticancer drug that inhibits the catalytic activity of DNA topoisomerase II (topo II) without damaging DNA or stabilizing DNA-topo II cleavable complexes. Although the cytotoxicity of the complex-stabilizing DNA-topo II inhibitors such as VP-16 (etoposi...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1999-03-01 00:00:00
abstract：:In previous studies, it was shown that the overexpression of beta2-adrenoceptor (beta2AR) in the hearts of transgenic mice (Tg) leads to agonist-independent activation of adenylate cyclase and enhanced myocardial function. Here, we measured the physical coupling of beta2AR and Gs by evaluating the coimmunoprecipitatio...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.52.2.187
更新日期：1997-08-01 00:00:00
abstract：:We studied the mechanism by which the peptide omega-grammotoxin-SIA inhibits voltage-dependent calcium channels. Grammotoxin at concentrations of > 50 nM completely inhibited inward current carried by 2 mM barium through P-type channels in rat cerebellar Purkinje neurons when current was elicited by depolarizations up...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.52.6.1095
更新日期：1997-12-01 00:00:00
abstract：:As a member of the transient receptor potential (TRP) ion channel superfamily, the ligand-gated ion channel TRPA1 has been implicated in nociceptive function and pain states. The endogenous ligands that activate TRPA1 remain unknown. However, various agonists have been identified, including environmental irritants (e....
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.106.033621
更新日期：2007-05-01 00:00:00
abstract：:Tumor suppressor gene BRCA1 is frequently mutated in familial breast and ovarian cancer. BRCA1 plays pivotal roles in maintaining genomic stability by interacting with numerous proteins in cell cycle control and DNA repair. Irofulven (6-hydroxymethylacylfulvene, HMAF, MGI 114, NSC 683863) is one of a new class of anti...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.106.029504
更新日期：2007-04-01 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：:Noscapine, a microtubule-interfering agent, has been shown to arrest mitosis, to induce apoptosis, and to have potent antitumor activity. We report herein that two brominated derivatives of noscapine, 5-bromonoscapine (5-Br-nosc) and reduced 5-bromonoscapine (Rd 5-Br-nosc), have higher tubulin binding activity than no...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.63.4.799
更新日期：2003-04-01 00:00:00
abstract：:Comparative molecular field analysis (CoMFA) predicts that the large electrostatic field around the phosphate groups of ATP plays a crucial role in stabilizing the open state of the cardiac ryanodine receptor (RyR) channel. We therefore investigated the effects of adenosine-5'-(beta,gamma-methylenetriphosphate) (AMP-P...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.63.1.174
更新日期：2003-01-01 00:00:00
abstract：:Five separate guanine nucleotide-binding proteins (G proteins) were immunologically identified in membranes from neuroblastoma x glioma NG108-15 hybrid cells. These alpha subunit proteins were Gi2 alpha, two isoforms of Gi3 alpha, and two isoforms of Go alpha. The G proteins that interacted with delta-opioid receptors...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1992-05-01 00:00:00
abstract：:The powerful analgesic effects of opioid drugs have captivated the interest of physicians and scientists for millennia, and the ability of opioid drugs to produce serious undesired effects has been recognized for a similar period of time (Kieffer and Evans, 2009). Many of these develop progressively with prolonged or ...
journal_title：Molecular pharmacology
pub_type： 杂志文章,评审
doi：10.1124/mol.119.119321
更新日期：2020-10-01 00:00:00
abstract：:ORKAMBI, a combination of the corrector, lumacaftor, and the potentiator, ivacaftor, partially rescues the defective processing and anion channel activity conferred by the major cystic fibrosis-causing mutation, F508del, in in vitro studies. Clinically, the improvement in lung function after ORKAMBI treatment is modes...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.119.117143
更新日期：2019-10-01 00:00:00
abstract：:Large conductance, Ca(2+)-activated K+ channels are believed to underlie interburst intervals and, thus, contribute to the control of hormone release from neurohypophysial terminals. Because ethanol inhibits the release of vasopressin and oxytocin, we studied its effects on large conductance, Ca(2+)-activated K+ chann...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1996-01-01 00:00:00
abstract：:We determined the effect of flufenamic acid (FFA) and related derivatives on gap junction channel currents, applying the dual whole-cell patch-clamp technique to pairs of N2A neuroblastoma cells transfected with various connexins. FFA reduced gap junction channel currents in a reversible and concentration-dependent ma...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.63.6.1389
更新日期：2003-06-01 00:00:00
abstract：:AM1710 (3-(1,1-dimethyl-heptyl)-1-hydroxy-9-methoxy-benzo(c) chromen-6-one), a cannabilactone cannabinoid receptor 2 (CB2) agonist, suppresses chemotherapy-induced neuropathic pain in rodents without producing tolerance or unwanted side effects associated with CB1 receptors; however, the signaling profile of AM1710 re...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.118.113233
更新日期：2019-02-01 00:00:00
abstract：:This study describes experiments investigating the mechanism of activation of A1 adenosine receptors. Isolated rat fat cells were used as a cellular model. The A1 receptors of these cells were covalently labeled with the agonist photoaffinity label R-2-azido-N6-p-hydroxyphenylisopropyladenosine. The covalent incorpora...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1986-10-01 00:00:00
abstract：:Dietary lipids and fat-soluble micronutrients are solubilized in mixed micelles and absorbed in the small intestine. Based on an assumption that cholesterol and other fat-soluble molecules share a number of transport mechanisms and the fact that Niemann-Pick C1-like 1 (NPC1L1) is critical for intestinal cholesterol ab...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.107.043034
更新日期：2008-07-01 00:00:00
abstract：:We have synthesized and characterized a high-affinity alpha 1-adrenergic receptor probe, 4-amino-6,7-dimethoxy-2[4'- [5"(3"'-125I-iodo-4"'-aminophenyl)pentanoyl]-1'-piperazinyl] quinazoline (125I-A55453). This ligand binds reversibly to rat hepatic plasma membranes with high affinity (KD = 77 +/- 6 pM), and it labels ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1984-09-01 00:00:00
abstract：:Cyclic nucleotide phosphodiesterases (PDEs) from canine trachealis were characterized with respect to their kinetic properties, sensitivity to selective inhibitors, and subcellular distribution. Extracts from whole tissue homogenates were applied to DEAE-Sepharose anion exchange columns and eluted with a linear sodium...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1990-02-01 00:00:00
abstract：:Iron-loading diseases remain an important problem because of the toxicity of iron-catalyzed redox reactions. Iron loading occurs in the mitochondria of Friedreich's ataxia (FA) patients and may play a role in its pathogenesis. This suggests that iron chelation therapy could be useful. We developed previously the lipop...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.108.046847
更新日期：2008-07-01 00:00:00
abstract：:Neuroactive steroids bind to a unique site on the gamma-aminobutyric acidA (GABAA) receptor complex and allosterically modulate the binding of convulsant ([35S]t-butylbicyclophosphorothionate, [35S]TBPS), GABA ([3H]muscimol), and benzodiazepine ([3H]flunitrazepam) site ligands. In rat cortical membranes, 3 alpha-hydro...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1996-05-01 00:00:00
abstract：:Previously we demonstrated that aldehyde dehydrogenase (ALDH) 1a1 is the major ALDH expressed in mouse liver and is an effective catalyst in metabolism of lipid aldehydes. Quantitative real-time polymerase chain reaction analysis revealed a ≈2.5- to 3-fold induction of the hepatic ALDH1A1 mRNA in mice administered eit...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.112.078147
更新日期：2012-10-01 00:00:00
abstract：:We examined the block of N-methyl-D-aspartate (NMDA) receptors by n-alkyl (straight chain) diamines and related monoamines and triamines using whole-cell voltage clamp recording of NMDA receptor currents in cultured rat hippocampal neurons and [3H] dizocilpine binding to rat forebrain homogenates. At -60 mV, the diami...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1994-01-01 00:00:00
abstract：:The cDNAs for the four murine aryl hydrocarbon (Ah) receptor alleles were cloned and sequenced, and the deduced amino acid sequences were compared. The Ahb-1 allele encodes a protein of 805 amino acids, the Ahd and Ahb-2 alleles encode proteins of 848 amino acids, and the Ahb-3 allele encodes a protein of 883 amino ac...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1994-11-01 00:00:00
abstract：:Nefiracetam (DM-9384) is a new pyrrolidone nootropic drug being developed for the treatment of Alzheimer's type and poststroke vascular-type dementia. Because the cholinergic system plays an important role in cognitive functions and Alzheimer's disease dementia, the present study was conducted to elucidate the mechani...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.59.4.674
更新日期：2001-04-01 00:00:00
abstract：:Reversible binding of warfarin to defatted serum albumin was studied by equilibrium dialysis at pH 7.4, in a 66 mM sodium phosphate buffer at 37 degrees. The binding isotherm could be described by two stoichiometric binding constants, K1 in the range 141,000 to 192,000 M-1 and K2 at 39,000 to 57,000 M-1. At least two ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1985-02-01 00:00:00
abstract：:The bisdioxopiperazines such as (+)-(S)-4,4'-propylenedi-2,6-piperazinedione (dexrazoxane; ICRF-187), 1,2-bis(3,5-dioxopiperazin-1-yl)ethane (ICRF-154), and 4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione (ICRF-193) are agents that inhibit eukaryotic topoisomerase II, whereas their ring-opened hydrolysis pro...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.107.036970
更新日期：2007-10-01 00:00:00
abstract：:Adefovir dipivoxil [9-(2-(bispivaloyloxymethyl)phosphonylmethoxyethyl)adenine (bis-POM PMEA)], an oral prodrug of adefovir (PMEA), is currently in phase III clinical testing for the treatment of human immunodeficiency virus-1 (HIV-1) infection. Previous in vitro experiments have shown that HIV-1 recombinant viruses ex...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.54.2.291
更新日期：1998-08-01 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：:Adenosine receptors of the A1 and A2 subtypes were characterized in membranes from DDT1 MF-2 smooth muscle cells. These cells possess a high density of A1 adenosine receptors (Bmax = 0.8-0.9 pmol/mg of protein), as measured by both agonist and antagonist radioligands. Agonists compete for [125I]N6-[2-(4-amino-3-iodoph...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1990-02-01 00:00:00
abstract：:Multidrug resistance-associated protein 2 (MRP2) transports glutathione conjugates, glucuronide conjugates, and sulfated conjugates of bile acids. In the present study, we examined the role of charged amino acids in the transmembrane domains of rat Mrp2, conserved among MRP families, using the isolated membrane vesicl...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.59.5.1077
更新日期：2001-05-01 00:00:00
