Abstract：
:Taxanes act by inhibiting microtubule dynamics; in this study, we have investigated mitochondria as an additional target of taxanes. We incubated isolated mitochondria in the presence of taxanes with or without stimulation of the mitochondrial respiratory state. Results showed that they rapidly induced the loss of deltapsim after stimulation of the respiratory state. To evaluate the binding of [14C]paclitaxel to isolated mitochondria, mitochondrial proteins were precipitated yielding 18.6 +/- 2.1 cpm/microg of protein. After stimulation of the respiratory state, binding of [14C]paclitaxel increased up to 163.2 +/- 46.7 cpm/microg of protein. CPM values after Bcl-2 immunoprecipitation was 62.8-fold higher than those of the control antibody, thereby indicating the involvement of Bcl-2 in paclitaxel binding. Then, we established a panel of A2780 cell lines resistant to increasing doses of paclitaxel alone or to high doses of paclitaxel/cyclosporin A (A2780 TC cells). In both cases, Bcl-2 expression was consistently down-regulated, whereas levels of other members of the Bcl-2 family, such as Bax and Bcl-x, did not change in paclitaxel-resistant cell lines. When A2780TC cells were stably transfected with a Bcl-2 construct, paclitaxel sensitivity was partially restored, thereby supporting a direct role of Bcl-2 down-regulation in the maintenance of drug-resistance. Finally, we examined Bcl-2 by immunohistochemistry in a small subset of ovarian cancer paclitaxel-resistant patients and we noticed that the protein is down-regulated in this clinical setting with respect to the expression levels found in drug-sensitive tumors. These findings demonstrate that Bcl-2 is an additional intracellular target of taxanes and that its down-regulation is involved in taxane resistance.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Ferlini C,Raspaglio G,Mozzetti S,Distefano M,Filippetti F,Martinelli E,Ferrandina G,Gallo D,Ranelletti FO,Scambia Gdoi
10.1124/mol.64.1.51keywords:
subject
Has Abstractpub_date
2003-07-01 00:00:00pages
51-8issue
1eissn
0026-895Xissn
1521-0111pii
64/1/51journal_volume
64pub_type
杂志文章abstract：:Human and bovine dopamine transporters (DAT) demonstrate discrete functional differences in dopamine (DA), 1-methyl-4-phenylpyridium (MPP(+)) transport, and cocaine analog binding. In a previous study, the functional analyses on the chimeras of human and bovine DAT have revealed that the region from residues 133 throu...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：2000-05-01 00:00:00
abstract：:TWIK-related K+ channel TREK1, a background leak K+ channel, has been strongly implicated as the target of several general and local anesthetics. Here, using the whole-cell and single-channel patch-clamp technique, we investigated the effect of lidocaine, a local anesthetic, on the human (h)TREK1 channel heterologousl...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.109.056838
更新日期：2009-10-01 00:00:00
abstract：:We have found that stypoldione, a bright red o-quinone isolated from the brown alga Stypopodium zonale, inhibits the division of sea urchin embryos in a concentration-dependent manner (IC50 approximately 2.5 X 10(-6) M). Although previous studies have shown this marine natural product to inhibit beef brain microtubule...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1983-11-01 00:00:00
abstract：:This study assessed how conformational information encoded by ligand binding to δ-opioid receptors (DORs) is transmitted to Kir3.1/Kir3.2 channels. Human embryonic kidney 293 cells were transfected with bioluminescence resonance energy transfer (BRET) donor/acceptor pairs that allowed us to evaluate independently reci...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.112.081950
更新日期：2013-02-01 00:00:00
abstract：:Regulators of G-protein signaling (RGS) proteins are important components of signal transduction pathways initiated through G-protein-coupled receptors (GPCRs). RGS proteins accelerate the intrinsic GTPase activity of G-protein alpha-subunits (Galpha) and thus shorten the time course and reduce the magnitude of G-prot...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.106.028670
更新日期：2007-01-01 00:00:00
abstract：:Previously, we reported the presence of dual promoters, referred to as distal (DP) and proximal, with a negative regulatory element between them in the mouse mu-opioid receptor (mor) gene. Here we have identified a positive regulatory element influencing mor DP transcription, which contains multiple consensus binding ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.59.6.1486
更新日期：2001-06-01 00:00:00
abstract：:Caveolins have been recognized over the past few decades as key regulators of cell physiology. They are ubiquitously expressed and regulate a number of processes that ultimately impact efficiency of cellular processes. Though not critical to life, they are central to stress adaptation in a number of organs. The follow...
journal_title：Molecular pharmacology
pub_type： 杂志文章,评审
doi：10.1124/mol.117.111237
更新日期：2018-04-01 00:00:00
abstract：:Ethanol administration to rats by ethanol vapor inhalation (14 days) results in a 40-50% reduction in the level of gamma-aminobutyric acidA (GABAA) receptor alpha 1 subunit mRNAs [4.4 and 4.8 kilobases (kb)] in the cerebral cortex. The level of alpha 2 subunit mRNA (8.0 kb) was also reduced by 29%, whereas there was n...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1991-02-01 00:00:00
abstract：:A high cytoplasmic Na(+) concentration may contribute to N-methyl-D-aspartate (NMDA)-induced excitotoxicity by promoting Ca(2+) influx via reverse operation of the Na(+)/Ca(2+) exchanger (NaCaX), but may simultaneously decrease the electrochemical Ca(2+) driving force by depolarizing the plasma membrane (PM). Digital ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.56.3.619
更新日期：1999-09-01 00:00:00
abstract：:Avermectins are a family of potent broad-spectrum anthelmintic compounds, which bind with high affinity to membranes isolated from the free-living nematode Caenorhabditis elegans. Binding of avermectins is thought to modulate chloride channel activity, but the exact mechanism for anthelmintic activity remains to be de...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1991-09-01 00:00:00
abstract：:The rat mu-opioid receptor clone in which novel exon 5 was found in the place of exon 4 (MOR-1B) was one of the first MOR-1 variants described. We now have identified the mouse homolog of the rat MOR-1B as well as four additional variants derived from splicing from exon 3 into different sites within exon 5. The sequen...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.105.011858
更新日期：2005-09-01 00:00:00
abstract：:Combining chemotherapeutics to treat malignant tumors has been shown to be effective in preventing drug resistance, tumor recurrence, and reducing tumor size. We modeled combination drug therapy in PC-3 human prostate cancer cells using mixture design response surface methodology (MDRSM), a statistical technique desig...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.117.111450
更新日期：2018-08-01 00:00:00
abstract：:The aim of this study was to create and characterize constitutively active mutant (CAM) histamine H(1) receptors (H(1)R) using random mutagenesis methods to further investigate the activation process of the rhodopsin-like family of G protein-coupled receptors (GPCRs). This approach identified position 6.40 in TM 6 as ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.107.038547
更新日期：2008-01-01 00:00:00
abstract：:Na+-d-glucose cotransporter 1 (SGLT1) is rate-limiting for glucose absorption in the small intestine. Shortly after intake of glucose-rich food, SGLT1 abundance in the luminal membrane of the small intestine is increased. This upregulation occurs via glucose-induced acceleration of the release of SGLT1-containing vesi...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.116.104521
更新日期：2016-11-01 00:00:00
abstract：:The CYP2C genes are extensively regulated at the transcriptional stage. The present study shows for the first time that CYP2Cs are also regulated post-transcriptionally by microRNAs (miRNAs). By using online search engines, we found potential miRNA response elements (MREs) in the 3'-untranslated region (3'-UTR) of the...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.112.078386
更新日期：2012-09-01 00:00:00
abstract：:The orphan nuclear receptor liver receptor homolog 1 (LRH-1; NR5A2) is a potent regulator of cholesterol metabolism and bile acid homeostasis. Recently, LRH-1 has been shown to play an important role in intestinal inflammation and in the progression of estrogen receptor positive and negative breast cancers and pancrea...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.114.095554
更新日期：2015-02-01 00:00:00
abstract：:The presence of DNA damage initiates signaling through the ataxia-telangiectasia mutated kinase (ATM) and the ATM- and the Rad3-related kinase (ATR), which phosphorylate, thus activating, the checkpoint kinases (Chk) 1 and 2, which leads to cell cycle arrest. The bifunctional DNA alkylator 1,3-bis(2-chloroethyl)-1-nit...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.108.053124
更新日期：2009-06-01 00:00:00
abstract：:Very few antagonists have been identified for the human pregnane X receptor (PXR). These molecules may be of use for modulating the effects of therapeutic drugs, which are potent agonists for this receptor (e.g., some anticancer compounds and macrolide antibiotics), with subsequent effects on transcriptional regulatio...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.108.049437
更新日期：2008-09-01 00:00:00
abstract：:Chick brain mRNA was isolated and injected into Xenopus oocytes. This led to the expression of gamma-aminobutyrate (GABA) channels easily accessible for current measurements using the voltage clamp technique. The effect of the anthelmintic natural product avermectin B1a on the GABA current was studied quantitatively. ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1987-12-01 00:00:00
abstract：:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was found to activate protein kinases under cell- and nucleus-free conditions in isolated C57 mouse liver cytosol (100,000 x g supernatant). This action of TCDD was found to be aryl hydrocarbon receptor (AHR) dependent, concentration dependent, and inhibited by genistein, a t...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.52.4.667
更新日期：1997-10-01 00:00:00
abstract：:We describe the structural and functional features of the human alpha3 nicotinic receptor subunit promoter. A 0.35-kb region immediately upstream of the start codon was identified that when transfected in human neuroblastoma cells was able to drive the expression of the luciferase reporter gene with a strength compara...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.51.2.250
更新日期：1997-02-01 00:00:00
abstract：:At the vertebrate neuromuscular junction (nmj), ATP is known to be coreleased with acetylcholine from the synaptic vesicles. We have previously shown that the P2Y1 receptor is localized at the nmj. Here, we extend the findings to show that another nucleotide receptor, P2Y2, is also localized there and with P2Y1 jointl...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.104.003269
更新日期：2004-10-01 00:00:00
abstract：:We used transcript-specific oligonucleotides to examine the localization in the rat nervous system of the corresponding mRNAs for the two P2X purinoceptor genes cloned recently from the rat vas deferens and PC12 cells. PC12 P2X purinoceptor mRNA was labeled in the olfactory tubercle, striatum, hypothalamus, hippocampu...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1995-10-01 00:00:00
abstract：:Variant neuroblastoma cell clones were selected for resistance to the cytotoxic effects of neurotoxins that cause persistent activation of sodium channels. Three classes of variant clones were obtained: sodium channel-deficient clones, which have markedly reduced numbers of functional sodium channels; scorpion toxin-r...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1982-07-01 00:00:00
abstract：:In the last years, reactive oxygen species (ROS) have been proposed as mediators of proliferative/hypertrophic responses to angiotensin II (Ang II), both in vivo and in vitro. However, the hypothesis that the Ang II-dependent cell contraction could be mediated by ROS, particularly H2O2, has not been tested. Present ex...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.59.1.104
更新日期：2001-01-01 00:00:00
abstract：:The effect of relatively nontoxic levels of HgCl2 on semiconservative DNA synthesis and on DNA repair induced following treatment of intact cells with X-ray or ultraviolet (UV) light has been studied in cultured Chinese hamster ovary cells. In the presence of 1 microM HgCl2 the repair of DNA strand breaks induced by 4...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1986-02-01 00:00:00
abstract：:The anti-arrhythmic quinidine has been reported to be a competitive inhibitor of the catalytic activities of human liver P-450DB, including sparteine delta 2-oxidation and bufuralol 1'-hydroxylation, and we confirmed the observation that submicromolar concentrations are strongly inhibitory. Human liver microsomes oxid...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1986-09-01 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：:G protein-coupled receptors (GPCRs) contribute to the regulation of every aspect of human physiology and are therapeutic targets for the treatment of numerous diseases. As a consequence, understanding the myriad of mechanisms controlling GPCR signaling and trafficking is essential for the development of new pharmacolo...
journal_title：Molecular pharmacology
pub_type： 杂志文章,评审
doi：10.1124/mol.115.098509
更新日期：2015-10-01 00:00:00
abstract：:The X-ray structure of the bacterial sodium channel NavAb provides a new template for the study of sodium and calcium channels. Unlike potassium channels, NavAb contains P2 helices in the outer-pore region. Because the sequence similarity between eukaryotic and prokaryotic sodium channels in this region is poor, the s...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.112.078212
更新日期：2012-07-01 00:00:00
