Abstract:
:The identification of proliferation/survival pathways constitutively activated by genetic alterations in multiple myeloma (MM), or sustained by the bone marrow (BM) microenvironment, provides novel opportunities for the development of targeted therapies. The deregulated function of protein tyrosine kinases plays a critical role in driving MM malignant phenotype. We investigated the effects of the multi-target tyrosine kinase inhibitor RPI-1 in a panel of human MM cell lines, including t(4;14) positive cell lines expressing the TK receptor FGF-R3. Cells harboring FGF-R3 activating mutations (KMS11 and OPM2) displayed the highest sensitivity to RPI-1 antiproliferative effect. The stimulating effect of the aFGF ligand was abrogated in cells harboring a non-constitutively active receptor. Drug treatment inhibited activation and expression of the FGF-R3(Y373C) mutant as well as aFGF-dependent signaling involving AKT and ERKs. Inhibition of JAK2, an additional RPI-1 target, resulted in STAT3 inactivation. Blockade of these proliferation/survival pathways was associated with caspase-dependent apoptosis. Moreover, drug treatment abrogated proliferative and pro-invasive stimuli provided by conditioned medium from mesenchymal stromal cells. Gene expression profile of KMS11 cells showed 22 upregulated and 52 downregulated genes upon RPI-1 treatment, with an early modulation of genes implicated in MM pathobiology such as SAT-1, MYC, MIP-1alpha/beta, FGF-R3, and the growth factor receptor B-cell maturation antigen (BCMA). Thus, concomitant blockade of FGF-R3 and JAK2 results in inhibition of several MM-promoting pathways, including BCMA-regulated signaling, and downregulation of disease-associated proteins. These data may have therapeutic implications in the design of treatment strategies resulting in the concomitant inhibition of FGF-R3 and JAK2 signaling pathways in t(4;14) MM.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Cassinelli G,Ronchetti D,Laccabue D,Mattioli M,Cuccuru G,Favini E,Nicolini V,Greco A,Neri A,Zunino F,Lanzi Cdoi
10.1016/j.bcp.2009.06.023subject
Has Abstractpub_date
2009-11-01 00:00:00pages
1139-47issue
9eissn
0006-2952issn
1873-2968pii
S0006-2952(09)00492-4journal_volume
78pub_type
杂志文章abstract::Mercaptomethylimidazole (MMI), a potent antithyroid drug of the thionamide group, induces both acid and pepsinogen secretion independently in control and pylorus ligated mice. The effect is dose dependent and the drug is more effective than histamine, carbachol or isoproterenol when administered by an intraperitoneal ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(90)90498-a
更新日期:1990-09-01 00:00:00
abstract::The effect of the anti-tumor, anti-glutamine drug acivicin, L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid, was determined on the activity of the rate-limiting enzyme of de novo pyrimidine biosynthesis, carbamoyl-phosphate synthetase II (glutamine-hydrolyzing) (EC 6.3.5.5), in human colon carci...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(85)90106-6
更新日期:1985-01-01 00:00:00
abstract::OSI-930, a dual c-Kit and KDR tyrosine kinase inhibitor, is reported to have undergone a Phase I dose escalation study in patients with advanced solid tumors. A series of fifteen pyridyl and phenyl analogues of OSI-930 were designed and synthesized. Extensive screening of these compounds led to the discovery that nitr...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2012.06.019
更新日期:2012-09-15 00:00:00
abstract::The experiments were designed to investigate some details of the action of 3-methylcholanthrene (3-MC) on the regulation of transcription. After a single intraperitoneal dose of 3-MC a significant increase in the activities of both nucleolar and nucleoplasmic protein kinases in hepatic cells of young rats was found. T...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(82)90343-4
更新日期:1982-03-15 00:00:00
abstract::Gemcitabine (dFdC) is a new cytidine analogue which is active mainly by the incorporation of its triphosphate (dFdCTP) into DNA, leading to cell death. We determined incorporation of dFdC into nucleic acids of two solid tumour cell lines: the murine colon carcinoma cell line Colon 26-10, the human ovarian carcinoma ce...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(93)90566-f
更新日期:1993-08-17 00:00:00
abstract::The beta 2-adrenoceptor agonist, clenbuterol (initially 5 mg/kg), was found to significantly reduce plasma tyrosine and raise brain tryptophan levels (P less than 0.01). By comparison, decreases in plasma tryptophan and increases in brain tyrosine were small and often nonsignificant. Amino acid levels measured in diff...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(89)90003-8
更新日期:1989-09-15 00:00:00
abstract::Neutrophil accumulation response to cigarette smoke (CS) in humans and animal models is believed to play an important role in pathogenesis of many tobacco-related lung diseases. Here we evaluated the lung anti-inflammatory effect of aspirin and indomethacin in mice exposed to CS. C57BL/6 mice were exposed to four ciga...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2008.12.012
更新日期:2009-03-15 00:00:00
abstract::Staurosporine is one of the most potent and well known inhibitors of protein kinases, and it is often used to study the involvement of protein kinases in signal transduction pathways. We now report that staurosporine can induce the production of hepatocyte growth factor (HGF) independently of protein kinase inhibition...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(03)00547-1
更新日期:2003-11-01 00:00:00
abstract::Boldine ([S]-2,9-dihydroxy-1,10-dimethoxyaporphine) has been shown to exert antioxidant and anti-inflammatory effects. The present study elucidated the protective effect of boldine on catecholamine-induced membrane permeability transition in brain mitochondria and viability loss in PC12 cells. Dopamine (200 microM) an...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(01)00852-8
更新日期:2002-02-01 00:00:00
abstract::Raf kinase inhibitor protein (RKIP) is a member of the phosphatidylethanolamine-binding protein (PEBP) family. RKIP plays a pivotal modulatory role in several protein kinase signaling cascades. RKIP binds inhibits Raf-1-mediated phosphorylation of MEK through binding to Raf-1. Protein kinase C (PKC) phosphorylates RKI...
journal_title:Biochemical pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.bcp.2004.04.024
更新日期:2004-09-15 00:00:00
abstract::Structure-activity studies on a series of analogues of N-(3-methyl-S-(1-pyrrolidinyl carbonyl) butyl)-D-alanine ethyl ester hydrochloride (SC42619) have defined the features of this dipeptide analogue required for observation of thrombin receptor antagonist activity on the human platelet. The affinity for SC42619, and...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(90)90037-l
更新日期:1990-01-15 00:00:00
abstract::Most anti-inflammatory agents used in the treatment of joint diseases exert inhibitory effects on leukocyte infiltration. Methotrexate, a disease-modifying drug, and corticosteroids also inhibit leukocyte accumulation during inflammation. However, the mechanisms of action of these different compounds on leukocytes var...
journal_title:Biochemical pharmacology
pub_type: 杂志文章,评审
doi:10.1016/s0006-2952(99)00056-8
更新日期:1999-07-15 00:00:00
abstract::Radioligand binding techniques are commonly used in the characterization of beta-adrenergic receptors on human peripheral leukocytes. Accurate interpretation of receptor binding parameters necessitates appropriate radioligand selection. In addition, cell isolation techniques should have minimal effect on the binding p...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(87)90041-4
更新日期:1987-05-15 00:00:00
abstract::Stimulation of lipolysis in murine adipocytes in response to a lipid-mobilizing factor produced by a cachexia-inducing murine adenocarcinoma was inhibited by eicosapentaenoic acid (EPA) with a Ki value of 104 microM. The inhibitory effect was strictly structurally specific, since other related fatty acids of both the ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(91)90016-x
更新日期:1991-01-01 00:00:00
abstract::[Carboxyl-14C] labelled 1,2,3,4-tetrahydro-beta-carboline-1-carboxylic acid (I) and 1-methyl-1,2,3,4-tetrahydro-beta-carboline-1-carboxylic acid (II) were synthesized and their decarboxylation was studied in mouse brain homogenate and buffer. The decarboxylation rates of (I) and (II) in the homogenate were about 6-fol...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(86)90173-5
更新日期:1986-08-15 00:00:00
abstract::Tannins are polyphenols commonly found in plant-derived foods. When ingested they can have various harmful effects, but salivary proline-rich proteins (PRPs) may provide protection against dietary tannins. The aim of this study was to investigate whether basic PRPs, a major family of salivary proteins, can prevent int...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2006.02.013
更新日期:2006-05-28 00:00:00
abstract::Glucocorticoids (GCs) are steroid hormones widely used as coadjuvants in the treatment of solid tumors due to their anti-inflammatory effects. However, evidence show that they also may induce chemotherapy resistance, probably through their capacity to inhibit apoptosis triggered by antineoplastic drugs. GCs exert thei...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2014.04.006
更新日期:2014-06-15 00:00:00
abstract::Neutrophils play a key role in host defense and inflammation through the production of superoxide anion and other reactive oxygen species (ROS) by the enzyme complex NADPH oxidase. The cytosolic NADPH oxidase component, p67phox, has been shown to be phosphorylated in human neutrophils but the pathways involved in this...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2011.07.070
更新日期:2011-11-01 00:00:00
abstract::The activity of tyrosine hydroxylase (TH) in the corpus striatum of haloperidol treated and control rats has been examined. The activation of TH by haloperidol caused a decrease in the Km for tetrahydrobiopterin but no change in the Vmax. This effect was totally abolished when homogenates were prepared at high values ...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(83)90364-7
更新日期:1983-11-15 00:00:00
abstract::What does it mean to be a mentor in science? Definitions of mentorship are freely spouted in publications and include concepts such as academic support, professional development, role modeling, interaction, impartment of knowledge, evaluation of work, demonstration of methodology, etc. Perhaps most of us would agree w...
journal_title:Biochemical pharmacology
pub_type: 传,历史文章,杂志文章,评审
doi:10.1016/j.bcp.2015.06.025
更新日期:2015-11-15 00:00:00
abstract::The inhibitory effects of quinolone antimicrobial agents and nonsteroidal anti-inflammatory drugs on purified mouse liver mitochondrial medium chain acyl-CoA synthetase catalyzing the first reaction of glycine conjugation were examined, using hexanoic acid as a substrate. Enoxacin, ofloxacin, nalidixic acid, diflunisa...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(01)00667-0
更新日期:2001-08-01 00:00:00
abstract::Our studies suggest that the fluctuation of HDC activity in fetal liver in late gestation is regulated by the plasma glucocorticoid level through the pituitary-adrenal system. Taken together, these results support the conclusion that glucocorticoid promotes a rapid increase in HDC synthesis in fetal liver histamine-fo...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(91)90092-j
更新日期:1991-03-01 00:00:00
abstract::BLT2, a low-affinity leukotriene B4 (LTB4) receptor, is a member of the G-protein coupled receptor (GPCR) family and is involved in the pathogenesis of inflammatory diseases such as asthma. Despite its clinical implications, however, no pharmacological inhibitors are available. In the present study, we screened for sm...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2010.01.018
更新日期:2010-05-15 00:00:00
abstract::In this paper, we illustrate how a proteomic analysis can be useful to approach complex biological problems, in this case the concept of stress-induced premature senescence (SIPS). According to the stochastic theories of ageing, damage that accumulate with time in the cellular components are responsible for cellular a...
journal_title:Biochemical pharmacology
pub_type: 杂志文章,评审
doi:10.1016/s0006-2952(02)01171-1
更新日期:2002-09-01 00:00:00
abstract::Gram-negative bacilli have become increasingly resistant to antibiotics over the past 2 decades due to selective pressure from the extensive use of antibiotics in the hospital and community. In addition, these bacteria have made optimum use of their innate genetic capabilities to extensively mutate structural and regu...
journal_title:Biochemical pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.bcp.2005.11.006
更新日期:2006-03-30 00:00:00
abstract::Rat aortic smooth muscle cells in culture (A-10; ATCC CRL 1476) exhibited low levels of beta-adrenergic receptors as determined by specific binding of [125I]cyanopindolol ([125I]CYP) and marginal stimulation of adenylate cyclase in plasma membranes by (-)isoproterenol. When these cells were exposed to 5 mM sodium buty...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/0006-2952(86)90669-6
更新日期:1986-11-01 00:00:00
abstract::Novel therapies for the treatment of solid tumors have generally failed to improve patient overall survival. These therapeutic approaches are typically focused on targeting signaling pathways implicated in cell growth and/or survival in order to shrink the malignant mass and achieve an objective clinical response; how...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2009.03.020
更新日期:2009-08-15 00:00:00
abstract::The present investigation addressed the role of verapamil for oral pharmacokinetics of morphine-6-beta-glucuronide (M6G). Male Sprague-Dawley rats received 62.5 mg kg(-1) M6G-dihydrate orally w/wo pre-treatment with 70 mg kg(-1) verapamil. Intravenous M6G (3.9 mg kg(-1) ) and oral morphine (52.7 mg kg(-1) morphine-hyd...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/s0006-2952(02)00881-x
更新日期:2002-04-15 00:00:00
abstract::Tumor necrosis factor-alpha (TNF-alpha) is a mediator of multiple inflammatory diseases. Vascular endothelial growth factor (VEGF) plays a critical role in TNF-alpha-mediated diseases. We investigated the inhibitory effects of 3,3',4',5,5',7-hexahydroxyflavone (myricetin), an abundant natural flavonoid, on TNF-alpha-i...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2008.10.027
更新日期:2009-02-01 00:00:00
abstract::We have investigated the ability of certain dietary flavonoids, known to exert beneficial effects on the central nervous system, to affect neuronal apoptosis. We used cerebellar granule cells undergoing apoptosis due to potassium deprivation in a serum-free medium in either the absence or presence of the flavonoids ge...
journal_title:Biochemical pharmacology
pub_type: 杂志文章
doi:10.1016/j.bcp.2009.10.005
更新日期:2010-03-01 00:00:00