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Statements

Subject Item
n2:RIV%2F00216208%3A11310%2F14%3A10288485%21RIV15-MSM-11310___
rdf:type
n8:Vysledek skos:Concept
rdfs:seeAlso
http://dx.doi.org/10.1371/journal.pone.0107367
dcterms:description
Attachment of stem leukemic cells to the bone marrow extracellular matrix increases their resistance to chemotherapy and contributes to the disease persistence. In chronic myelogenous leukemia (CML), the activity of the fusion BCR-ABL kinase affects adhesion signaling. Using real-time monitoring of microimpedance, we studied in detail the kinetics of interaction of human CML cells (JURL-MK1, MOLM-7) and of control BCR-ABL-negative leukemia cells (HEL, JURKAT) with fibronectin-coated surface. The effect of two clinically used kinase inhibitors, imatinib (a relatively specific c-ABL inhibitor) and dasatinib (dual ABL/SRC family kinase inhibitor), on cell binding to fibronectin is described. Both imatinib and low-dose (several nM) dasatinib reinforced CML cell interaction with fibronectin while no significant change was induced in BCR-ABL-negative cells. On the other hand, clinically relevant doses of dasatinib (100 nM) had almost no effect in CML cells. The efficiency of the inhibitors in blocking the activity of BCR-ABL and SRC-family kinases was assessed from the extent of phosphorylation at autophosphorylation sites. In both CML cell lines, SRC kinases were found to be transactivated by BCR-ABL. In the intracellular context, EC50 for BCR-ABL inhibition was in subnanomolar range for dasatinib and in submicromolar one for imatinib. EC50 for direct inhibition of LYN kinase was found to be about 20 nM for dasatinib and more than 10 mu M for imatinib. Cells pretreated with 100 nM dasatinib were still able to bind to fibronectin and SRC kinases are thus not necessary for the formation of cell-matrix contacts. However, a minimal activity of SRC kinases might be required to mediate the increase in cell adhesivity induced by BCR-ABL inhibition. Indeed, active (autophosphorylated) LYN was found to localize in cell adhesive structures which were visualized using interference reflection microscopy. Attachment of stem leukemic cells to the bone marrow extracellular matrix increases their resistance to chemotherapy and contributes to the disease persistence. In chronic myelogenous leukemia (CML), the activity of the fusion BCR-ABL kinase affects adhesion signaling. Using real-time monitoring of microimpedance, we studied in detail the kinetics of interaction of human CML cells (JURL-MK1, MOLM-7) and of control BCR-ABL-negative leukemia cells (HEL, JURKAT) with fibronectin-coated surface. The effect of two clinically used kinase inhibitors, imatinib (a relatively specific c-ABL inhibitor) and dasatinib (dual ABL/SRC family kinase inhibitor), on cell binding to fibronectin is described. Both imatinib and low-dose (several nM) dasatinib reinforced CML cell interaction with fibronectin while no significant change was induced in BCR-ABL-negative cells. On the other hand, clinically relevant doses of dasatinib (100 nM) had almost no effect in CML cells. The efficiency of the inhibitors in blocking the activity of BCR-ABL and SRC-family kinases was assessed from the extent of phosphorylation at autophosphorylation sites. In both CML cell lines, SRC kinases were found to be transactivated by BCR-ABL. In the intracellular context, EC50 for BCR-ABL inhibition was in subnanomolar range for dasatinib and in submicromolar one for imatinib. EC50 for direct inhibition of LYN kinase was found to be about 20 nM for dasatinib and more than 10 mu M for imatinib. Cells pretreated with 100 nM dasatinib were still able to bind to fibronectin and SRC kinases are thus not necessary for the formation of cell-matrix contacts. However, a minimal activity of SRC kinases might be required to mediate the increase in cell adhesivity induced by BCR-ABL inhibition. Indeed, active (autophosphorylated) LYN was found to localize in cell adhesive structures which were visualized using interference reflection microscopy.
dcterms:title
Real-Time Analysis of Imatinib- and Dasatinib-Induced Effects on Chronic Myelogenous Leukemia Cell Interaction with Fibronectin Real-Time Analysis of Imatinib- and Dasatinib-Induced Effects on Chronic Myelogenous Leukemia Cell Interaction with Fibronectin
skos:prefLabel
Real-Time Analysis of Imatinib- and Dasatinib-Induced Effects on Chronic Myelogenous Leukemia Cell Interaction with Fibronectin Real-Time Analysis of Imatinib- and Dasatinib-Induced Effects on Chronic Myelogenous Leukemia Cell Interaction with Fibronectin
skos:notation
RIV/00216208:11310/14:10288485!RIV15-MSM-11310___
n3:aktivita
n12:S
n3:aktivity
S
n3:cisloPeriodika
9
n3:dodaniDat
n5:2015
n3:domaciTvurceVysledku
n14:7087543
n3:druhVysledku
n11:J
n3:duvernostUdaju
n19:S
n3:entitaPredkladatele
n17:predkladatel
n3:idSjednocenehoVysledku
41491
n3:idVysledku
RIV/00216208:11310/14:10288485
n3:jazykVysledku
n10:eng
n3:klicovaSlova
resistance; expression; hematopoiesis; adhesion; src; cancer-cells; integrin function; bcr-abl; tyrosine kinase inhibitors; chronic myeloid-leukemia
n3:klicoveSlovo
n4:expression n4:src n4:tyrosine%20kinase%20inhibitors n4:bcr-abl n4:cancer-cells n4:resistance n4:chronic%20myeloid-leukemia n4:integrin%20function n4:adhesion n4:hematopoiesis
n3:kodStatuVydavatele
US - Spojené státy americké
n3:kontrolniKodProRIV
[F276250EF40F]
n3:nazevZdroje
PLoS ONE
n3:obor
n16:EA
n3:pocetDomacichTvurcuVysledku
1
n3:pocetTvurcuVysledku
4
n3:rokUplatneniVysledku
n5:2014
n3:svazekPeriodika
9
n3:tvurceVysledku
Obr, Adam Roeselová, Pavla Grebeňová, Dana Kuželová, Kateřina
n3:wos
000341304700107
s:issn
1932-6203
s:numberOfPages
11
n7:doi
10.1371/journal.pone.0107367
n18:organizacniJednotka
11310