Abstract:
:Human ABCG2 is a plasma membrane glycoprotein that provides physiological protection against xenobiotics. ABCG2 also significantly influences biodistribution of drugs through pharmacological tissue barriers and confers multidrug resistance to cancer cells. Moreover, ABCG2 is the molecular determinant of the side population that is characteristically enriched in normal and cancer stem cells. Numerous tumors depend on unregulated EGFR signaling, thus inhibition of this receptor by small molecular weight inhibitors such as gefitinib, and the novel second generation agents vandetanib, pelitinib and neratinib, is a promising therapeutic option. In the present study, we provide detailed biochemical characterization regarding the interaction of these EGFR inhibitors with ABCG2. We show that ABCG2 confers resistance to gefitinib and pelitinib, whereas the intracellular action of vandetanib and neratinib is unaltered by the presence of the transporter. At higher concentrations, however, all these EGFR inhibitors inhibit ABCG2 function, thereby promoting accumulation of ABCG2 substrate drugs. We also report enhanced expression of ABCG2 in gefitinib-resistant non-small cell lung cancer cells, suggesting potential clinical relevance of ABCG2 in acquired drug resistance. Since ABCG2 has important impact on both the pharmacological properties and anti-cancer efficiencies of drugs, our results regarding the novel EGFR inhibitors should provide useful information about their therapeutic applicability against ABCG2-expressing cancer cells depending on EGFR signaling. In addition, the finding that these EGFR inhibitors efficiently block ABCG2 function may help to design novel drug-combination therapeutic strategies.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Hegedüs C,Truta-Feles K,Antalffy G,Várady G,Német K,Ozvegy-Laczka C,Kéri G,Orfi L,Szakács G,Settleman J,Váradi A,Sarkadi Bdoi
10.1016/j.bcp.2012.04.010subject
Has Abstractpub_date
2012-08-01 00:00:00pages
260-7issue
3eissn
0006-2952issn
1873-2968pii
S0006-2952(12)00290-0journal_volume
84pub_type
杂志文章abstract::Several derivatives of N-t-butyl-alpha-phenylnitrone (PBN) such as N-2-(2-ethoxycarbonyl-propyl)-alpha-phenylnitrone (EPPN) have recently been reported to form superoxide spin adducts (t(1/2) ca. 2-7 min at pH 7.0), which are considerably more stable than their respective PBN or DMPO adducts (t(1/2) ca. 10 and 45 s, r...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2004.03.017
更新日期:2004-07-01 00:00:00
abstract::High-affinity binding of [3H](+/-)2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene [( 3H]-ADTN) was improved by use of a subcellular fraction (P4) of tissue obtained from calf brain. The highest concentration of binding sites was found in caudate nucleus which was evaluated extensively. Binding of 0.5 nM [3H]-ADTN ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(83)90391-x
更新日期:1983-10-01 00:00:00
abstract::The major populations of cholinergic neurons in the brain include two "projection" systems, located in the pontine reticular formation and in the basal forebrain. These two complexes comprise, in part, the anatomical substrates for the "ascending reticular activating system" (ARAS). The pontine cholinergic system rela...
journal_title:Biochemical pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.bcp.2005.05.019
更新日期:2005-10-15 00:00:00
abstract::Tumor-induced neoangiogenesis is an essential event for solid tumor growth. Therefore, a compound able to block angiogenesis-promoting factors could have antitumor activity. The polysulfonated naphthylurea suramin is hypothesized to have this mode of action. A series of sulfonated distamycin A derivatives have been sy...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(94)90020-5
更新日期:1994-01-20 00:00:00
abstract::Recently, the marked decline in renal carnitine reabsorption has been thought to account fotr the systemic carnitine deficiency in juvenile visceral steatosis (JVS) mice. We have conducted a kinetic analysis using embryonic fibroblasts derived from normal, heterozygous, and homozygous jvs mice and found that the high-...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(97)00670-9
更新日期:1998-05-15 00:00:00
abstract::JG-03-14, a substituted pyrrole that inhibits microtubule polymerization, was screened against MCF-7 (p53 wild type), MDA-MB231 (p53 mutant), MCF-7/caspase 3 and MCF-7/ADR (multidrug resistant) breast tumor cell lines. Cell viability and growth inhibition were assessed by the crystal violet dye assay. Apoptosis was ev...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2007.07.003
更新日期:2007-10-01 00:00:00
abstract::Reduced glutathione is nitrosated in aerobic solutions of nitric oxide under physiological conditions; however, the extent of S-nitrosation was found to be dependent on the inorganic anions present. Of nine anions tested, the bifunctional anions, arsenate, phosphate, and pyrophosphate (40 mM), inhibited the S-nitrosat...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(96)00825-8
更新日期:1997-02-21 00:00:00
abstract::We have reported previously that both dietary iron and selenium regulate intestinal cytochrome P-450 content by modulating the synthesis of its prosthetic heme moiety. Whether these elements are required for synthesis and/or viability of its apocytochrome moiety is unknown. We have examined the effects of intraluminal...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(85)90252-7
更新日期:1985-03-01 00:00:00
abstract::Tirapazamine (SR 4233) is a bioreductive antitumour drug in Phase III clinical trial which is activated in hypoxic tumour regions to generate a cytotoxic species. Electron paramagnetic resonance (EPR) spectrometry was used to investigate directly the formation of free radicals as the result of tirapazamine reduction b...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(00)00487-1
更新日期:2000-12-15 00:00:00
abstract::Intact brain cell aggregates were dissociated from adult rat brains, by a simple sieving technique, and were used to study the binding characteristics of [3H]N-methylscopolamine to muscarinic acetylcholine receptors. The magnitude of binding of this ligand was related linearly to the amount of cell protein in the bind...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(85)90288-6
更新日期:1985-12-15 00:00:00
abstract::Phenylbutyrate has been shown recently to induce fetal hemoglobin (HbF) production in patients with sickle cell anemia and beta thalassemia. We have now examined related aromatic fatty acids in order to define the range of active structures and identify plausible mechanisms of action. Structure-function analysis revea...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(96)00476-5
更新日期:1996-10-25 00:00:00
abstract::Guanidines, amidines, S-alkylisothioureas, and other compounds containing the amidine function (-C(=NH)NH2) have been described as inhibitors of the generation of nitric oxide (NO) by NO synthase (NOS). Here we report on the inhibition of the activity of NOS isoforms by compounds in which the amidine function is attac...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(97)00196-2
更新日期:1997-08-01 00:00:00
abstract::To assess the relative contributions that the sodium channel blocking activity of propranolol may play in a variety of its therapeutic applications, its effects were examined in vitro with a sodium channel specific 22Na+ uptake system, using rat brain membranes. Propranolol inhibited 22Na+ uptake in the rat brain memb...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(82)90668-2
更新日期:1982-05-01 00:00:00
abstract::Administration of non-cholestatic doses of manganese (Mn2+) followed by injection of bilirubin (BR) results in a severe reduction in rat bile flow. Male Sprague-Dawley rats were given various doses of Mn2+ (2, 4.5, 8, and 18 mg/kg, i.v.) and killed 0.25, 1, 3, or 5 hr later. 54Mn2+ was used to evaluate Mn2+ content (m...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(85)90435-6
更新日期:1985-11-01 00:00:00
abstract::Induction of cytosolic long-chain acyl-CoA hydrolases was investigated in rat liver after administration of various peroxisome proliferators and related compounds. Treatment of rats with di-(2-ethylhexyl)-phthalate, di-(2-ethylhexyl)-adipate or tiadenol induced hydrolases I and II, while acetylsalicylic acid induced o...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(84)90517-3
更新日期:1984-04-01 00:00:00
abstract::Phenylbutazone (PBZ) is known to inhibit the oriented migration of human polymorphonuclear leukocytes (PMNs) induced by formyl-methionyl-leucyl-phenylalanine (FMLP), and to protect these cells against the deactivation caused by their prior incubation with FMLP. To gain insight into the mechanism of these effects, we m...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(82)90082-x
更新日期:1982-10-01 00:00:00
abstract::Using a continuous perfusion system, synaptosomes prepared from rat brain released [3H]norepinephrine in a Ca2+-dependent manner when pulse depolarized by briefly elevating external potassium concentrations. Tetrodotoxin (10(-7) M), a sodium channel blocker, inhibited 48% of this pulsed release, and D595 (10(-5) M), a...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(89)90460-7
更新日期:1989-07-15 00:00:00
abstract::Innovative crystallographic techniques have resulted in an exponential growth in the number of solved G-protein coupled receptor (GPCR) structures and a better understanding of the mechanisms of class A receptor activation and G protein binding. The recent release of the type 1 receptor for the corticotropin-releasing...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2015.05.015
更新日期:2015-08-01 00:00:00
abstract::The oxazaphosphorine agent cyclophosphamide (CP) is an alkylating agent with a relative low stem cell toxicity. The aim of this study was to further evaluate the stem cell toxicity of the active metabolites of CP and its structural analogue ifosfamide (IFO) in comparison to their antileukemic efficacy. Cells of differ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(02)00868-7
更新日期:2002-04-01 00:00:00
abstract::Although it is known that the pathogenic mechanism of Helicobacter pylori involves the stimulated production of interleukin-8 (IL-8) as an inflammatory mediator, the details of the pathway remain unclear. The role of mitogen-activated protein kinase (MAPK) in IL-8 production by H. pylori has been examined in an in vit...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(01)00628-1
更新日期:2001-06-15 00:00:00
abstract::The expression of xenobiotic-metabolising cytochrome P450 proteins in the liver of cattle was determined using substrate probes and immunologically by Western blot analysis. Compared to the rat, cattle displayed much higher coumarin 7-hydroxylase (CYP2A) and ethoxyresorufin O-deethylase (CYP1) activity but, in contras...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(01)00710-9
更新日期:2001-09-01 00:00:00
abstract::The GABA(B) receptor antagonist SGS742 (CGP36742) displays pronounced cognition enhancing effects in mice, young and old rats and in Rhesus monkeys in active and passive avoidance paradigms, in an eight-arm radial maze and a Morris water maze and in a social learning task. SGS742 blocks the late inhibitory postsynapti...
journal_title:Biochemical pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1016/j.bcp.2004.07.030
更新日期:2004-10-15 00:00:00
abstract::Adiponectin blocks hepatocellular carcinoma (HCC) progression by inducing cell apoptosis through the modulation of C-Jun N-terminal kinase and mammalian target of rapamycin. However, the precise upstream signaling pathways or molecules remain elusive. In the present study, we analyzed the role of antioxidant protein t...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2014.12.001
更新日期:2015-01-15 00:00:00
abstract::Alterations in heme biosynthetic and degradative capabilities and in the activities of several heme-containing enzymes were examined in hepatic tissues of streptozotocin (STZ)-diabetic female Sprague-Dawley rats. Activities were measured 10, 30 and 90 days following the administration of STZ (65 mg/kg, i.v.). The acti...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(83)90059-x
更新日期:1983-06-15 00:00:00
abstract::Targeting of deregulated protein tyrosine kinases has been proposed as a new approach in the therapeutic intervention against pathological processes including proliferative disorders and cancer. Using a screening approach based on a comparative evaluation of antiproliferative effects in a panel of tumor cells with dif...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(00)00278-1
更新日期:2000-06-15 00:00:00
abstract::Aldehyde dehydrogenase (ALDH) is well known for its involvement in the resistance of tumor cells to cyclophosphamide (CPA) and its activated derivatives, such as 4-hydroperoxy-CPA (4HC). The role of other drug-metabolizing enzymes such as glutathione S-transferase (GST) in CPA resistance is, however, less certain. In ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(95)00079-f
更新日期:1995-05-26 00:00:00
abstract::In this study we compared two methods, electron spin resonance (ESR) spectroscopy and high performance liquid chromatography (HPLC), which are currently used to detect directly hydroxyl radical (OH.) formation in the ischemic and reperfused heart. Isolated buffer-perfused rat hearts were subjected to 30 min of normoth...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(93)90182-v
更新日期:1993-02-24 00:00:00
abstract::The proinflammatory cytokine interleukin (IL)-18 appears to be involved in the pathogenesis of diseases associated with immunoactivation and inflammation. Consequently, blockage of IL-18 bioactivity by use of IL-18 binding protein (IL-18 BP) is likely a promising therapeutic concept. In the present study, we investiga...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(03)00294-6
更新日期:2003-08-01 00:00:00
abstract::The binding of nimodipine, a 1,4-dihydropyridine Ca2+ channel antagonist, and of Bay K 8644, a Ca2+ channel activator, was measured in several regions of rat brain and compared to the distribution of K+ depolarization-induced 45Ca2+ uptake into synaptosomes. The maximum binding densities (Bmax) of [3H]nimodipine and [...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(87)90575-2
更新日期:1987-12-01 00:00:00
abstract::The oxidative metabolism of more than 20 drugs (e.g. sparteine, debrisoquine, dextromethorphan) is mediated by cytochrome P450IID6. Codeine O-demethylation to morphine was recently demonstrated to co-segregate with the polymorphic metabolism of debrisoquine and dextromethorphan. The female Dark-Agouti rat (DA) is an a...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(91)90077-i
更新日期:1991-03-01 00:00:00