Abstract:
:The underlying mechanism of the antiproliferative effect of S (simvastatin), a HMG-CoA reductase inhibitor, in vascular smooth muscle cells (SMC) is still poorly understood. In the present study, we used synchronized human SMC, isolated from left interior mammary artery, as an in vitro model to test the effects of S on platelet-derived growth factor (PDGF)-induced DNA synthesis, extracellular-regulated kinase 1/2 (ERK1/2), p38/stress-activated protein kinase 2 (SAPK2), RhoA and Rac1 activation. ERK1/2 phosphorylation was triggered within 2 min of PDGF stimulation (early G1 phase) and was blocked by PD98059, a specific inhibitor of the ERK1/2 pathway, which also strongly inhibited PDGF-induced DNA synthesis (IC(50) = 10 micromol/L). PDGF quickly induced p38 phosphorylation (early G1 phase) and SB203580, a specific inhibitor of the p38/SAPK2 pathway, also blocked PDGF-induced DNA synthesis (IC(50) = 0.3 micromol/L). Translocation to the plasma membrane of small GTPases, such as RhoA and Rac1, could not be detected within 15 min of stimulation with PDGF or lysophosphatidic acid (LPA) (early G1 phase), but occurred after 24 hr of PDGF stimulation (late G1/S phase). S inhibited PDGF-induced DNA synthesis (IC(50) = 3.5 micromol/L), and this effect was dependent on intracellular mevalonate, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate availability. The critical time period for the reversal of the S effect by mevalonate comprised both the early and late G1 phase of the SMC cycle. PDGF-induced ERK1/2 phosphorylation and PDGF-induced p38 phosphorylation were not markedly affected by S during the whole G1 phase. However, S treatment blocked the PDGF- and LPA-induced membrane translocation of RhoA that occurred during the late G1/S phase. In the case of Rac1, the same process was also inhibited by S treatment. We concluded from these results that, in SMC, the early events associated with ERK1/2 and p38 signal transduction pathways, recruited for PDGF-mediated DNA synthesis, were insensitive to S action, whereas the mevalonate-dependent, posttranslational modification of RhoA and Rac1 molecules, required for PDGF-induced membrane translocation, was blocked by this drug. These results suggest that the antiproliferative effect of S can be explained not only by the blockage of RhoA-mediated signaling events but also by Rac1-mediated signaling events.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Nègre-Aminou P,van Erck M,van Leeuwen RE,Collard JG,Cohen LHdoi
10.1016/s0006-2952(01)00566-4subject
Has Abstractpub_date
2001-04-15 00:00:00pages
991-8issue
8eissn
0006-2952issn
1873-2968pii
S0006-2952(01)00566-4journal_volume
61pub_type
杂志文章abstract::To derive structure/function relationships for muscarinic receptor/G-protein coupling, the m2 and m5 muscarinic receptors and a series of m2/m5 chimeras were tested for agonist binding and functional responses in a cellular proliferation/transformation assay. m5, which mediates stimulation of phosphatidylinositol turn...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(95)02234-1
更新日期:1996-02-23 00:00:00
abstract::3'-Azido-2',3'-dideoxy-5-iodouridine (AzIdUrd) and 3'-azido-2',3'-dideoxy-5-bromouridine (AzBdUrd), previously shown to be potent and selective inhibitors of human immunodeficiency virus replication in vitro were minimally toxic to the uninfected human lymphoid cell line H9 (IC50 = 197 and 590 microM, respectively). B...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(93)90396-e
更新日期:1993-01-07 00:00:00
abstract::We employed both [5-3H] ara-C and ([2-14C] ara-C labeled L1210 DNA for analysis following exposure to alkali under various conditions. The results demonstrated that the tritium label on C5 of ara-C molecules incorporated in DNA was exchanged with water under alkaline conditions and, therefore, radioactivity was subseq...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(82)90475-0
更新日期:1982-03-01 00:00:00
abstract::The antitumor activity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) has been shown previously to be enhanced markedly by the co-administration of pyrimidine deoxyribonucleosides (Lin and Prusoff, Cancer Res 47: 394-397, 1987). In the present study, we examined the cellular mechanisms underlying the augmentation effe...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(96)00905-7
更新日期:1997-03-07 00:00:00
abstract::Opiates act through a specific receptor to inhibit the striatal adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4,6.1.1] and stimulate a high-affinity GTPase (EC 3.6.1). The present study analyzes the functions of the striatal adenylate cyclase complex following chronic morphine treatment in the rat. The in...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(88)90507-2
更新日期:1988-03-15 00:00:00
abstract::Understanding the mechanism of resistance to tubulin-targeted anticancer drugs is important for improved chemotherapy. In this work, a colchicine-resistant MCF-7 cell line (MCF-7Col30) was generated by the gradual increment of colchicine treatment and the MCF-7Col30 showed ∼8-fold resistance towards colchicine. MCF-7C...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2017.02.018
更新日期:2017-05-15 00:00:00
abstract::Adenosine triphosphate (ATP) is a molecule that on one hand plays a central role in cellular energetics and which on the other is a ubiquitous signaling molecule when released into the extracellular media. Extracellular ATP accumulates in inflammatory environments where it acts as a damage-associated molecular pattern...
journal_title:Biochemical pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.bcp.2020.114385
更新日期:2020-12-20 00:00:00
abstract::Previously, we reported that the multidrug resistance proteins MRP1, MRP2 and MRP3 confer resistance to therapeutic antifolates by mediating their cellular extrusion. We now determined whether MRPs also play a role in controlling cellular homeostasis of natural folates. In MRP1, MRP2 and MRP3-transfected 2008 human ov...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(02)01615-5
更新日期:2003-03-01 00:00:00
abstract::The in vivo actions of two antimetabolites, acivicin (NSC-163501) and tiazofurin (NSC-286193), were examined on the enzymic programs of rat bone marrow. From the bone marrow of the femurs, 100,000 g supernatant fractions were prepared; enzymic activities were measured by isotopic assays, and cellularity was determined...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(88)90175-x
更新日期:1988-03-01 00:00:00
abstract::"Ecstasy" [(+/-)-3,4-methylenedioxymethamphetamine or MDMA] is a CNS stimulant, whose use is increasing despite evidence of long-term neurotoxicity. In vitro, the majority of MDMA is demethylenated to (+/-)-3,4-dihydroxymethamphetamine (DHMA) by the polymorphic cytochrome P450 2D6 (CYP2D6). We investigated the demethy...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(02)01028-6
更新日期:2002-06-15 00:00:00
abstract::We tested the ability of a wide variety of organic compounds, including benzene and phenol derivatives, aromatic amines, pyrazoline derivatives and other non-steroidal anti-inflammatory drugs, to act as cosubstrates during the horseradish peroxidase/hydrogen peroxide-mediated oxygenation of arachidonic acid. Structura...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(89)90326-2
更新日期:1989-04-15 00:00:00
abstract::Melatonin (MEL) has been proposed as a therapeutic agent for the oral cavity, due to its antioxidant and anti-inflammatory effects since periodontal diseases are aggravated by free radicals, and by disproportionate immunological response to plaque microorganism. In addition, MEL promotes bone formation. This study aim...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2013.10.009
更新日期:2013-12-15 00:00:00
abstract::Foetal rat whole brain reaggregate cultures were prepared in a serum-supplemented (S+) or serum-free medium (S-). Ethylcholine mustard aziridinium (ECMA) was added to the cultures at 9 days in vitro (DIV) at concentrations of 12.5, 25 or 50 microM. Choline acetyltransferase (ChAT) activity was measured at +2, +48 and ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(89)90311-0
更新日期:1989-05-15 00:00:00
abstract::The triazolobenzodiazepine compound alprazolam may have unique clinical effects compared to other benzodiazepines, and both behavioral and neurochemical studies have indicated unusual results after acute doses of alprazolam. To determine the effects of chronic dosage in mice, alprazolam (2 mg/kg/day) was administered ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(89)90584-4
更新日期:1989-11-01 00:00:00
abstract::Ciprofibrate (CP), a peroxisome proliferator, has been shown to reduce rat liver endoplasmic reticulum (ER) Ca(2+)-ATPase activity both in vitro and in vivo. The ER Ca(2+)-ATPase is highly susceptible to thiol reactivity, and maintenance of maximal enzyme activity is critically dependent upon the integrity of these th...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(93)90021-n
更新日期:1993-05-25 00:00:00
abstract::Petrosaspongiolide M (PT) is a potent secretory phospholipase A(2) inhibitor and anti-inflammatory agent. This marine metabolite reduced the production of nitrite, prostaglandin E(2), and tumor necrosis factor-alpha in the mouse air pouch injected with zymosan. These effects were also observed in mouse peritoneal macr...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(02)01659-3
更新日期:2003-03-01 00:00:00
abstract::We investigated the interactions of 4'-(9-acridinylamino)methanesulfon-m-anisidide (mAMSA) with thiol-containing compounds and the potential binding of the thiolytic adducts to DNA. All thiols tested (glutathione, cysteine, coenzyme A, 2-mercaptoethanol and lactate dehydrogenase) formed adducts with mAMSA as evidenced...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(86)90319-9
更新日期:1986-05-15 00:00:00
abstract::Low molecular weight cadmium-binding proteins were studed in lung tissue from rabbits exposed to aerosols of CdCl2. Lungs obtained from animals exposed by inhalation to aerosols of 800 or 1600 micrograms/m3 CdCl2 for 2-hr periods/day, every other day for a 5-day period, were found to contain at least three low molecul...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(82)90271-4
更新日期:1982-09-15 00:00:00
abstract::A new type of low-molecular-weight heparin (ss-LMW-H) was prepared (by controlled depolymerization and concurrent sulfation of heparin with a mixture of sulfuric and chlorosulfonic acid), to test the influence of extra-sulfate groups on biological properties of heparin fragments. The fragments had an average molecular...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(87)90485-0
更新日期:1987-06-15 00:00:00
abstract::The capabilities of 1alpha, 25-dihydroxyvitamin D3 (1,25(OH)2D3), and two novel vitamin D analogues, EB1089 and KH1060, to induce the differentiation of two established leukaemia cell lines, U937 and HL-60, were assessed alone or in combination with the retinoid compounds, 9-cis retinoic acid (9-cis RA) and all-trans ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(97)00195-0
更新日期:1997-09-01 00:00:00
abstract::Incubation of rat peritoneal mast cells with hydrogen peroxide results in a marked release of histamine. Maximal release is observed with 0.05-0.1 mM H(2)O(2), but higher concentrations of H(2)O(2) instead suppresses the release. Histamine release starts after about 2 min of lag time and reaches a plateau in about 10 ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(80)90550-x
更新日期:1980-03-01 00:00:00
abstract::Major antidepressant agents increase synaptic levels of monoamines. Although the monoamine hypothesis of depression remains a cornerstone of our understanding of the pathophysiology of depression, emerging data has suggested that the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subtype of g...
journal_title:Biochemical pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.bcp.2005.12.022
更新日期:2006-04-28 00:00:00
abstract::Acetoacetyl-CoA synthetase (AACS, acetoacetate-CoA ligase, EC 6.2.1.16) is a ketone body-utilizing enzyme, the physiological role of which remains unclear yet in mammals, particularly has never been studied in human. In order to investigate the tissue distribution of AACS in human, cDNA encoding AACS was isolated from...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(02)01656-8
更新日期:2003-03-15 00:00:00
abstract::Entrectinib is a new tyrosine kinase inhibitor that was recently approved for the treatment of ROS1-positive metastatic non-small cell lung cancer (NSCLC). In this study, we aimed to characterize its potential to act as a modulator of pharmacokinetic cytostatic resistance and perpetrator of drug interactions. In accum...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2020.114061
更新日期:2020-08-01 00:00:00
abstract::The response and engagement of host normal tissues in malignant disease are major factors in therapeutic resistance. Physically, solid tumors have regions of hypoxia and acidosis. These physical stresses can lead to a more aggressive malignant phenotype through activation of HIF, GLUT-1, carbonic anhydrase IX, and sub...
journal_title:Biochemical pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.bcp.2009.01.006
更新日期:2009-06-01 00:00:00
abstract::Ginkgolide B (GKB, BN 52021) was described as a platelet-activating factor (Paf) receptor antagonist. However, it is not known whether all GKB biological effects are mediated through Paf receptor antagonism only. To gain insight into the drug mode of action, we investigated here the effects of GKB per se on functional...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(01)00866-8
更新日期:2002-04-01 00:00:00
abstract::There is intense interest in the development and application of animal models of CNS disorders to explore pathology and molecular mechanisms, identify potential biomarkers, and to assess the therapeutic utility, estimate safety margins and establish pharmacodynamic and pharmacokinetic parameters of new chemical entiti...
journal_title:Biochemical pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.bcp.2013.06.016
更新日期:2014-01-01 00:00:00
abstract::Uracil incorporation into DNA occurs under conditions that limit thymidine biosynthesis; uracil is removed by two isoforms of uracil DNA glycosylase (UNG; EC 3.2.2.3), UNG1 and UNG2. We hypothesize that UNG is important in protecting the mid-organogenesis stage [gestational day (GD) 10-12] rat conceptus against condit...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(02)01252-2
更新日期:2002-08-15 00:00:00
abstract::A marked inhibition of the growth of solid tumor adenocarcinoma 755 was achieved by the combination of 5-fluorouracil (5-FU) with bromovinyldeoxyuridine (BVDU). The therapeutic index (LD50/ED50) for the combination of BVDU plus 5-FU was 8.1 and 3.9 upon intraperitoneal (i.p.) or oral (p.o.) administration, respectivel...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(88)90025-1
更新日期:1988-04-15 00:00:00
abstract::Folate-binding protein (FBP), a high-affinity folate receptor, is responsible for cellular accumulation of folate and folate analogs such as methotrexate in human KB (nasopharyngeal carcinoma) cells. Both FBP and FBP mRNA increase 3- to 5-fold when KB cells are grown in folate-deficient (less than 10 nM folate) medium...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(93)90235-o
更新日期:1993-06-22 00:00:00