Abstract:
:Increasing evidence is accumulating that zoledronic acid (ZOL), a nitrogen-containing bisphosphonate (N-BP), is able to affect tumor cells by inhibiting the enzyme farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway (MVP). The consequent accumulation of unprenylated proteins is believed to largely account for the cytotoxic effects of ZOL. FPPS inhibition leads also to the accumulation of isopentenyl pyrophosphate (IPP) and the apoptotic ATP analog, ApppI, but the role of this mechanism in the cytotoxic action of bisphosphonates is less clear. Since treatment with MVP intermediates has been shown to overcome N-BP-induced apoptosis via rescuing protein prenylation, our aim here was to determine their mechanism of action on ZOL-induced IPP/ApppI accumulation. Interestingly, the results revealed that ZOL-induced IPP/ApppI accumulation in MCF-7 cells were decreased by farnesol, and almost completely blocked by geranylgeraniol and geranylpyrophosphate. The functionality of the regulatory enzymes of IPP and ApppI, IPP isomerase and aminoacyl-tRNA-synthase, respectively, or protein levels of FPPS were not affected by the treatments. However, the protein levels of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) and unprenylated Rap1A were observed to be strongly downregulated by geranylgeraniol and geranylpyrophosphate. This study represents a novel insight into the mechanism of action of MVP intermediates on the regulation of MVP after FPPS inhibition. The data implies that in addition to the previously reported effects on rescuing protein prenylation, MVP intermediates can preserve cell activity by inhibiting the accumulation of IPP/ApppI via HMGR downregulation. This supports the hypothesis that IPP/ApppI formation is a significant mechanism in the anticancer action of ZOL.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Räikkönen J,Mönkkönen H,Auriola S,Mönkkönen Jdoi
10.1016/j.bcp.2009.10.003subject
Has Abstractpub_date
2010-03-01 00:00:00pages
777-83issue
5eissn
0006-2952issn
1873-2968pii
S0006-2952(09)00855-7journal_volume
79pub_type
杂志文章abstract::Nitroimidazoles labeled with technetium-99m are being investigated as non-invasive markers of tumor hypoxia. They are bioreductive compounds that require enzymatic reduction for retention in hypoxic cells, but little is known about the cellular factors affecting their accumulation in hypoxic cells. If the absolute acc...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(00)00373-7
更新日期:2000-09-01 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::Inflammation-induced microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal enzyme that synthesizes prostaglandin E(2) (PGE(2)) downstream of cyclooxygenase-2 (COX-2). The efficacy of nonsteroidal anti-inflammatory drugs and COX-2 inhibitors in the treatment of the signs and symptoms of osteoarthritis, rheuma...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2010.01.003
更新日期:2010-05-15 00:00:00
abstract::Somatostatin receptors from rabbit retinal membranes were solubilized in an active form using a mixture of the detergent n-octyl b-D-glucopyranoside (OG) and CHAPS. The binding of [125I]-Try11-somatostatin to the soluble extract was saturable and of high affinity, with an apparent affinity constant (Kd) of 0.60 +/- 0....
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(93)90439-4
更新日期:1993-05-05 00:00:00
abstract::Dichlorodi[U-14C]phenyltrichloroethane ( [14C]DDT), incubated with rat hepatic microsomes and NADPH, produced reactive intermediates which covalently bound to microsomal protein and lipids. In atmospheric oxygen, DDT bound to microsomal protein; however, binding was increased up to approximately 70% by oxygen depletio...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(84)90483-0
更新日期:1984-01-15 00:00:00
abstract::Rat hepatic microsomes catalyzed the formation of two distinct glutathione conjugates of bilirubin dimethylester (DMB). The two conjugates were identical to those isolated from the bile of Gunn rats infused with DMB. The microsomal reaction was dependent on NADPH, oxygen and glutathione and was inhibited by nitrogen a...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(91)90597-x
更新日期:1991-10-24 00:00:00
abstract::Tenofovir alafenamide (TAF) can be considered a new prodrug of tenofovir (TFV), as successor of tenofovir disoproxil fumarate (TDF). It is in vivo as potent against human immunodeficiency virus (HIV) at a 30-fold lower dose (10mg) than TDF (300mg). TAF has been approved in November 2015 (in the US and EU), as a single...
journal_title:Biochemical pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.bcp.2016.04.015
更新日期:2016-11-01 00:00:00
abstract::In a series of colorectal cancer cell lines, both necrosis and apoptosis were induced upon exposure to oxaliplatin, and enhanced by co-administration of the Hsp90 inhibitor 17-AAG. We analyzed the effects of these interventions on the cell cycle, and found that oxaliplatin treatment caused G1 and G2 arrest in HCT116 c...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2007.01.037
更新日期:2007-06-01 00:00:00
abstract::Amodiaquine, a 4-aminoquinoline antimalarial, has been associated with hepatitis and agranulocytosis in humans. Drug hypersensitivity reactions, especially agranulocytosis, have been attributed to reactive intermediates generated by the oxidants discharged from stimulated polymorphonuclear leucocytes (PMN). The metabo...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(95)00236-s
更新日期:1995-09-28 00:00:00
abstract::The ability of adrenergic catechol derivatives, including dobutamine, dopamine, and isoproterenol, to inhibit lipid peroxidation was examined. All the catechol derivatives we tested strongly inhibited lipid peroxidation. Dobutamine was a more powerful inhibitor of iron-catalyzed lipid peroxidation than the other agent...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(98)00075-6
更新日期:1998-06-15 00:00:00
abstract::The tyrosine kinase inhibitors (TKIs) and multikinase inhibitors (MKIs) are oncology drugs of increasing importance that have improved the treatment of multiple tumors types. In some patients these agents produce adverse effects, including pharmacokinetic drug-drug interactions, due to cytochrome P450 (CYP) inhibition...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2014.01.016
更新日期:2014-03-15 00:00:00
abstract::Most human UDP-glucuronosyltransferase (UGT; EC 2.4.1.17) genes contain non-synonymous single nucleotide polymorphisms (nsSNPs) which cause amino acid substitutions. Allelic variants caused by nsSNPs may exhibit absent or reduced enzyme activity. UGT2B7 is one of the most important UGTs that glucuronidates abundant en...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2015.03.002
更新日期:2015-05-01 00:00:00
abstract::The use of either methadone or buprenorphine for treatment of the pregnant opiate-dependent patient improves maternal and neonatal outcome. However, patient outcomes are often complicated by neonatal abstinence syndrome (NAS). The incidence and severity of NAS should depend on opiate concentration in the fetal circula...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2009.07.002
更新日期:2009-11-01 00:00:00
abstract::Alpha2-adrenoceptor agents as well as stress affect the activity of several hepatic monoxygenases including those related to CYP1A enzymes. This study was therefore designed to assess the role of central and/or peripheral catecholamines and, in particular, of adrenoceptors in the regulation of B(alpha)P-induced cytoch...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2004.09.024
更新日期:2005-01-15 00:00:00
abstract::We report here studies on the regulation of the metabolism of adenosine 3',5'-monophosphate (cAMP) in established and primary cultures of rat pulmonary microvascular endothelial cells (RPMVEC). Inhibition by rolipram, a selective inhibitor of cAMP phosphodiesterase (PDE) of the PDE4 gene family, was required to achiev...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(01)00914-5
更新日期:2002-02-15 00:00:00
abstract::The effects of acute systemic injection of the D-1 agonist SKF 38393 (2.5-20 mg/kg) or the D-1 antagonist SCH 23390 (0.25-2.0 mg/kg), and of the D-2 agonist quinpirole (0.12-1.0 mg/kg) or the D-2 antagonist sulpiride (25-100 mg/kg) on the neuropeptide content of rat basal ganglia were investigated. In striatum, the [M...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(91)90112-i
更新日期:1991-05-01 00:00:00
abstract::Rhodamine 123 is a mitochondrial dye that is retained for prolonged periods by carcinoma cells. While investigating causes of retention of this dye, we found that 10 microM progesterone caused a rapid stimulation of efflux of rhodamine 123 within 15 min from KB V20C cells, which overexpress the multidrug resistance pu...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(93)90331-p
更新日期:1993-11-02 00:00:00
abstract::The mammalian thioredoxin reductase (TrxR) isoenzymes, TrxR1 in cytosol or nucleus, TrxR2 in mitochondria, and TrxR3 in testis, are essential seleno-flavoenzymes with a conserved penultimate selenocysteine (Sec) residue at the C-terminus, and have attracted increasing interests as potential targets for development of ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2015.12.004
更新日期:2016-02-15 00:00:00
abstract::The murine Cyp2a-4 and Cyp2a-5 genes encode P450 isoforms catalysing testosterone 15 alpha-hydroxylase and coumarin 7-hydroxylase (COH) activities, respectively. Two days after the administration of a hepatotoxic dose of cerium chloride (2 mg/kg i.v.), COH activity was increased 3.2-fold in the liver of DBA/2 mice. Th...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(92)90525-n
更新日期:1992-10-06 00:00:00
abstract::Sublines of K562 human leukemia cells were selected for resistance (30- to 80-fold) to etoposide by continuous exposure to 0.5 microM VP-16. Two etoposide-resistant cell lines, K/VP.5 and K/VP.5-1, showed a 5-fold reduction in levels of topoisomerase II alpha protein compared with K562 cells. Northern analysis indicat...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(93)90643-b
更新日期:1993-12-03 00:00:00
abstract::Cyclophosphamides are pro-drugs whose killing agent is produced from an aldehyde that is formed by the action of a P450 oxidation step. The mustard from the aldehyde can destroy bone marrow cells as well as the tumor. Aldehyde dehydrogenase (EC 1.2.1.3) can oxidize the aldehyde and hence inactivate the cytotoxic inter...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2008.06.018
更新日期:2008-09-01 00:00:00
abstract::The formation of morphine glucuronides is enantio- and regioselective in rats and humans. In rat liver microsomes, natural (-)-morphine formed only the 3-O-glucuronide, whereas the unnatural (+)-morphine formed glucuronides at both the 3-OH and 6-OH positions, with the 6-O-glucuronide being the principal product. In h...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(89)90625-4
更新日期:1989-10-01 00:00:00
abstract::The action of nystatin, a polyene antibiotic, was studied in rat myocardial cells, isolated rat hearts, and intact rats. Myocardial cells responded to 10 and 25 micrograms nystatin/ml with arrhythmias that could be minimized by elevated concentrations of K+ and Mg2+ or reversed by washing the cells. Similarly, the iso...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(84)90040-6
更新日期:1984-12-01 00:00:00
abstract::Hepatic microsomal preparations from male and female rats were delipidated by column chromatography following cholate solubilisation. The enzyme activities were reconstituted using known lipids and the vesicle reconstitution method. Enzyme activity was assayed using lignocaine as the substrate for the mixed function o...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(87)90071-2
更新日期:1987-04-15 00:00:00
abstract::The PI3K/AKT/mTOR signaling pathway regulates cell proliferation, survival and angiogenesis. The mammalian target of rapamycin (mTOR) is a protein kinase ubiquitously expressed within cells that regulates cell growth and survival by integrating nutrient and hormonal signals. mTOR exists in two complexes, mTORC1 and mT...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2011.11.027
更新日期:2012-02-15 00:00:00
abstract::The effect of macrophage supernatant on the recovery of wounds induced in rat gastric epithelial RGM1 monolayers was investigated. The repair of wounds induced in the monolayers of RGM1 cells was accelerated time-dependently by 10 ng/mL of transforming growth factor-alpha (TGF-alpha). TGF-alpha also significantly stim...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(99)00202-6
更新日期:1999-10-01 00:00:00
abstract::Chiral derivatives of several substituted halopyridyl and thiazolyl PETT compounds were synthesized as non-nucleoside inhibitors of the reverse transcriptase (RT) enzyme of the human immunodeficiency virus (HIV-1). Molecular modeling studies indicated that because of the asymmetric geometry of the non-nucleoside inhib...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2004.01.019
更新日期:2004-05-15 00:00:00
abstract::We have investigated the redox behavior of a series of structurally related flavonoids employing cyclic voltammetry under physiological conditions. The flavonoids that auto-oxidized and produced oxygen radicals had oxidation potentials (E 1/2) significantly lower [-30 to +60 mV vs (SCE)] than those that did not underg...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(88)90253-5
更新日期:1988-07-01 00:00:00
abstract::To identify needed human equilibrative nucleoside transporter 4 (hENT4) inhibitors, we cloned and stably expressed the recombinant protein in PK15NTD (nucleoside transporter deficient) cells, and, investigated its interaction with a series of dipyridamole analogs synthesized in our laboratory. Compounds were tested in...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2013.08.063
更新日期:2013-12-01 00:00:00
abstract::Duchenne muscular dystrophy (DMD) is caused by dystrophin deficiency, which results in muscle necrosis and the upregulation of heat shock/stress proteins (HSP). We hypothesized that reactive oxygen species, and in particular hydroxyl radicals (.OH), participate in muscle necrosis and HSP expression. It was assumed tha...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(98)00055-0
更新日期:1998-09-15 00:00:00