Abstract:
BACKGROUND AND PURPOSE:Pancreatic cancer is characterized by alterations in several key signalling proteins, including increased expression and activity of the Src tyrosine kinase and focal adhesion kinase (FAK), which have been linked to its chemoresistance. Sustained Src inhibition reactivates survival pathways regulated by the transcription factor STAT3, also leading to resistance. Therefore, simultaneously targeting Src/FAK and STAT3 signalling could provide an important strategy for treating pancreatic cancer. Recently, we described novel quinazolinediones that increased generation of reactive oxygen species (ROS) and were cytotoxic in pancreatic cancer cells. Here, we have investigated effects of our lead compound, QD232, on Src/FAK and STAT3 signalling. EXPERIMENTAL APPROACH:The major signalling pathways affected by QD232 in pancreatic cancer cell lines were identified by Kinexus proteomic analysis. Changes in key signalling proteins were confirmed by Western blotting. Cell migration was assessed by Boyden chamber and wound healing assays. Direct inhibition of kinase activity in vitro was assayed with a panel of 92 oncogenic kinases. Safety and efficacy of QD232 were determined in a xenograft mouse model of pancreatic cancer. KEY RESULTS:QD232 potently inhibited Src/FAK and STAT3 phosphorylation, decreasing pancreatic cancer cell viability and migration. Furthermore, QD232 arrested cell cycle progression and induced apoptosis in these cells at low micromolar concentrations. Effects of QD232 on Src/FAK and STAT3 phosphorylation were blocked by N-acetylcysteine or glutathione. CONCLUSIONS AND IMPLICATIONS:QD232 is a novel compound with a unique, ROS-dependent mechanism, effective in drug-resistant cancer cell lines. This compound shows potential as therapy for pancreatic cancer.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Pathania D,Kuang Y,Sechi M,Neamati Ndoi
10.1111/bph.12855subject
Has Abstractpub_date
2015-01-01 00:00:00pages
50-63issue
1eissn
0007-1188issn
1476-5381journal_volume
172pub_type
杂志文章abstract::The pharmacological activity of two natural bombesin-like peptides, alytesin and litorin, and 25 related synthetic peptides has been compared to that of bombesin. 2 The minimum length of the amino acid chain required for the first appearance of bombesin-like effects was represented by the C-terminal heptapeptide, and ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1975.tb07631.x
更新日期:1975-10-01 00:00:00
abstract::1. Ethanol has been reported to inhibit the induction of long-term potentiation (LTP) in the hippocampus. However, the correlation between the effects of ethanol in vivo and in vitro remained unclear. In addition, previous works have little considered the possibility that the effect of ethanol is mediated by its metab...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0702738
更新日期:1999-08-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Varenicline, a neuronal nicotinic acetylcholine receptor (nAChR) modulator, decreases ethanol consumption in rodents and humans. The proposed mechanism of action for varenicline to reduce ethanol consumption has been through modulation of dopamine (DA) release in the nucleus accumbens (NAc) via α...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.12690
更新日期:2014-07-01 00:00:00
abstract::1. Fenclozic acid (2-(4-chlorophenyl)thiazol-4-ylacetic acid; I.C.I. 54,450; "Myalex") is one representative of a new class of compounds with antiinflammatory, analgesic and antipyretic properties as evidenced by its activity in a variety of tests in rats, mice and guinea-pigs.2. In tests of short duration the potency...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1969.tb08290.x
更新日期:1969-03-01 00:00:00
abstract::1. The present study was undertaken to investigate the anti-inflammatory effects of a synthetic compound, LCY-2-CHO, on the expression of inducible nitric oxide synthase (iNOS), COX-2, and TNF-alpha in murine RAW264.7 macrophages. 2. Within 1-30 microm, LCY-2-CHO concentration-dependently inhibited lipopolysaccharide ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0705700
更新日期:2004-03-01 00:00:00
abstract:BACKGROUND AND PURPOSE:The endocannabinoid, anandamide, has anti-arrhythmic effects. The aim of the present study was to explore the electrophysiological effects of anandamide on rat myocardium. EXPERIMENTAL APPROACH:Evoked action potentials (APs) were recorded using intracellular recording technique in rat cardiac pa...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2009.00518.x
更新日期:2009-12-01 00:00:00
abstract::Ligands targeting GPCRs can be categorized according to their intrinsic efficacy to trigger a specific, receptor-mediated response. A ligand endowed with the same level of efficacy as the endogenous agonist can be classified as a full agonist, whereas a compound that displays greater efficacy, that is, higher receptor...
journal_title:British journal of pharmacology
pub_type: 杂志文章,评审
doi:10.1111/bph.13278
更新日期:2016-10-01 00:00:00
abstract::1. The effects of prejunctional beta-adrenoceptor activation on electrically evoked noradrenaline (NA) and adenosine 5'-triphosphate (ATP) were studied by use of continuous amperometry and conventional intracellular recording techniques. Excitatory junction potentials (e.j.ps) were used as a measure of ATP release, an...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0700959
更新日期:1997-03-01 00:00:00
abstract::1. In rat aortic rings contracted by phenylephrine, the relaxation induced by isoprenaline was partly inhibited by iberiotoxin, (ibTX), tetraethylammonium, 4-aminopyridine (4-AP) and 1,9-dideoxyforskolin, but not by glibenclamide. 2. In the presence of 4-AP, 1,9-dideoxyforskolin failed to inhibit further the relaxant ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1996.tb15700.x
更新日期:1996-10-01 00:00:00
abstract::The monamine oxidase (MAO) inhibitors harmaline, tranylcypromine, deprenyl, clorgyline and iproniazid were injected intraperitoneally for five days to rabbits at doses that produced significant MAO inhibition. The first three inhibitors raised the concentrations of pyruvate and lactate in blood, decreased the activity...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1985.tb11109.x
更新日期:1985-12-01 00:00:00
abstract::1. The pharmacological characteristics of RP 67580, a non-peptide tachykinin NK1 receptor antagonist, and its effects on a reflex response evoked by stimulation of primary afferent fibres, were examined in isolated neonatal spinal cord preparations of the rat. Potentials were recorded extracellularly from a lumbar ven...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb17116.x
更新日期:1994-12-01 00:00:00
abstract::1. The effects of a new kind of volatile anaesthetic, sevoflurane (Sev), on gamma-aminobutyric acid (GABA)-gated chloride current (Icl) in single neurones dissociated from the rat hippocampal CA1 area were examined using the nystatin perforated patch recording configuration under the voltage-clamp condition. All drugs...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1996.tb15772.x
更新日期:1996-11-01 00:00:00
abstract::Schizophrenia remains an elusive multifaceted disorder with all evidence of its onset and aetiology pointing to a complex interplay of genetic, nutritional, environmental and developmental factors. Although several molecular and structural abnormalities have been reported for schizophrenia, no diagnostic test or other...
journal_title:British journal of pharmacology
pub_type: 杂志文章,评审
doi:10.1038/sj.bjp.0707658
更新日期:2008-03-01 00:00:00
abstract::1. The aim of this study was to investigate whether the hypotensive effect of rat alpha-calcitonin gene-related peptide (alpha CGRP) in conscious rats is mediated by endothelium-derived nitric oxide (NO) or the opening of adenosine 5'-triphosphate (ATP)-sensitive potassium (KATP) channels. 2. Dose-mean arterial pressu...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1992.tb14290.x
更新日期:1992-05-01 00:00:00
abstract::1 The present study comprised treatment of healthy male rats with Delta(9)-tetrahydrocannabinol (THC, 10 mg kg(-1), p.o.), and combinations of THC with benzoflavone moiety (BZF, 10 and 20 mg kg(-1), p.o.) isolated from Passiflora incarnata Linneaus, over a period of 30 days. 2 Upon 30-days chronic administrations, the...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0705015
更新日期:2003-01-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Down's syndrome is a common genetic cause of intellectual disability, for which there are no drug therapies. Mechanistic studies in a model of Down's syndrome [Ts65Dn (TS) mice] demonstrated that impaired cognitive function was due to excessive neuronal inhibitory tone. These deficits were normal...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.12169
更新日期:2013-07-01 00:00:00
abstract::1. The effects of nipradilol, a beta-adrenoceptor antagonist which possesses a nitroxy group, on cytosolic Ca2+ concentration ([Ca2+]i), and on tension development were simultaneously measured by front-surface fluorometry and fura-2-loaded strips in the proximal portion of pig coronary arteries. 2. Nipradilol reduced ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1996.tb15343.x
更新日期:1996-04-01 00:00:00
abstract::1. We studied the effect of bradykinin on plasma exudation in the airways of the anaesthetized guinea-pig in vivo. Tissue content of extravasated Evans blue dye was used as an index of protein exudation in the larynx, trachea, main bronchi and intrapulmonary airways (i.p.a.). 2. Bradykinin increased the content of Eva...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1990.tb14150.x
更新日期:1990-11-01 00:00:00
abstract::1. Adult male rats were treated with propranolol (2.0 mg kg-1 day-1 i.p.), pindolol (0.2 mg kg-1 day-1 i.p.) or 0.9% NaCl day-1 i.p. and exposed to +4 degrees C for 42 days, or treated with 0.9% NaCl day-1 i.p. and kept at +23 degrees C for 42 days. They were weighed once a week, when a 24 h urine sample was also coll...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1990.tb12988.x
更新日期:1990-04-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Our team previously demonstrated that diabetes induces a deterioration in vascular dynamics, in parallel with the enhanced formation of advanced glycation end products. The aim of this study was to determine whether prevention of the arterial stiffening by pyridoxamine in diabetes is associated w...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2009.00309.x
更新日期:2009-08-01 00:00:00
abstract::Specific [125I]-angiotensin II (AII) and [125I]-bradykinin (Bk) binding sites have been identified within epithelial membranes from rat jejunum and descending colon. These high affinity intestinal sites exhibited KD values of 0.64 +/- 0.16 nM for [125I]-AII and 0.69 +/- 0.13 nM for [125I]-Bk, which were similar to tho...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1986.tb10172.x
更新日期:1986-01-01 00:00:00
abstract::A well-known nitric oxide (NO)-releasing compound, sodium nitroprusside (SNP), decreases in a dose-dependent manner NO synthase (NOS) activity induced in rat neutrophils by treatment with lipopolysaccharide (LPS). This inhibitory action of SNP seems not to be due to its direct effect on the enzyme activity. The strong...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1995.tb13320.x
更新日期:1995-03-01 00:00:00
abstract::1. In the present work, we have studied the expression of Fos during acute and chronic administration of the kappa-opioid receptor agonist U-50488H and after U-5088H withdrawal in the rat hypothalamic paraventricular nucleus (PVN). Fos production was also studied in brainstem regions that innervate the PVN: the A(2) c...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0705179
更新日期:2003-04-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Carboxylesterases (CEs) metabolize a wide range of xenobiotic substrates including heroin, cocaine, meperidine and the anticancer agent CPT-11. In this study, we have purified to homogeneity human liver and intestinal CEs and compared their ability with hydrolyse heroin, cocaine and CPT-11. EXPE...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2010.00700.x
更新日期:2010-08-01 00:00:00
abstract::1. The role of adrenal hormones in the regulation of the systemic and local production of tumour necrosis factor (TNF alpha) was examined in male Balb/c mice. 2. Intraperitoneal injection of 0.3 mg E. coli lipopolysaccharide (LPS, 0111:B4) led to high levels of circulating TNF alpha without stimulating TNF alpha produ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1996.tb15317.x
更新日期:1996-04-01 00:00:00
abstract::1. The mechanisms involved in tachykinin-induced oedema were investigated in rat skin and interactions between the tachykinins and calcitonin gene-related peptide (CGRP) were studied. 2. Intradermal injections of the tachykinins, substance P, neurokinin A and neurokinin B, stimulated local oedema formation which was i...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1989.tb11926.x
更新日期:1989-05-01 00:00:00
abstract::1. Adenosine A(1), A(2A), and A(3) receptors (ARs) and extracellular signal-regulated kinase 1/2 (ERK1/2) play a major role in myocardium protection from ischaemic injury. In this study, we have characterized the adenosine receptor subtypes involved in ERK1/2 activation in newborn rat cardiomyocytes. 2. Adenosine (non...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0705614
更新日期:2004-01-01 00:00:00
abstract::1 Twenty-two compounds classified as antidepressants, metabolites of antidepressants or putative antidepressants were assayed for their ability to antagonize the binding of (-)-[3H]-quinuclidinyl benzilate to muscarinic receptors in homogenates of human caudate nucleus. 2 Sixteen of these compounds were assayed for th...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:
更新日期:1983-01-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Memantine and ketamine are clinically used, open-channel blockers of NMDA receptors exhibiting remarkable pharmacodynamic similarities despite strikingly different clinical profiles. Although NMDA channel gating constitutes an important difference between memantine and ketamine, it is unclear how...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.13007
更新日期:2015-03-01 00:00:00
abstract::1. Sarcolemmal membranes were isolated from normal and from denervated muscles and the specific binding of [125I]-alpha-bungarotoxin to the membranes was determined. 2. Cytosol prepared from either slow (soleus) or fast (extensor digitorum longus) muscle increased the toxin binding. Similar effects were seen with cyto...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1988.tb11611.x
更新日期:1988-07-01 00:00:00