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Statements

Subject Item
n2:RIV%2F68378050%3A_____%2F13%3A00398210%21RIV14-AV0-68378050
rdf:type
n8:Vysledek skos:Concept
dcterms:description
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand with selective antitumor activity. However, many primary tumors are TRAIL resistant. Previous studies reported that roscovitine, a cyclin-dependent kinase inhibitor, sensitized various solid cancer cells to TRAIL. We show that roscovitine and TRAIL demonstrate synergistic cytotoxicity in hematologic malignant cell lines and primary cells. Pretreatment of TRAIL-resistant leukemia cells with roscovitine induced enhanced cleavage of death-inducing signaling complex-bound proximal caspases after exposure to TRAIL. We observed increased levels of both pro- and antiapoptotic BCL-2 proteins at the mitochondria following exposure to roscovitine. These results suggest that roscovitine induces priming of cancer cells for death by binding antiapoptotic BCL-2 proteins to proapoptotic BH3-only proteins at the mitochondria, thereby decreasing the threshold for diverse proapoptotic stimuli. We propose that the mitochondrial priming and enhanced processing of apical caspases represent major molecular mechanisms of roscovitine-induced sensitization to TRAIL in leukemia/lymphoma cells. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand with selective antitumor activity. However, many primary tumors are TRAIL resistant. Previous studies reported that roscovitine, a cyclin-dependent kinase inhibitor, sensitized various solid cancer cells to TRAIL. We show that roscovitine and TRAIL demonstrate synergistic cytotoxicity in hematologic malignant cell lines and primary cells. Pretreatment of TRAIL-resistant leukemia cells with roscovitine induced enhanced cleavage of death-inducing signaling complex-bound proximal caspases after exposure to TRAIL. We observed increased levels of both pro- and antiapoptotic BCL-2 proteins at the mitochondria following exposure to roscovitine. These results suggest that roscovitine induces priming of cancer cells for death by binding antiapoptotic BCL-2 proteins to proapoptotic BH3-only proteins at the mitochondria, thereby decreasing the threshold for diverse proapoptotic stimuli. We propose that the mitochondrial priming and enhanced processing of apical caspases represent major molecular mechanisms of roscovitine-induced sensitization to TRAIL in leukemia/lymphoma cells.
dcterms:title
Roscovitine sensitizes leukemia and lymphoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis Roscovitine sensitizes leukemia and lymphoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis
skos:prefLabel
Roscovitine sensitizes leukemia and lymphoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis Roscovitine sensitizes leukemia and lymphoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis
skos:notation
RIV/68378050:_____/13:00398210!RIV14-AV0-68378050
n8:predkladatel
n9:ico%3A68378050
n3:aktivita
n14:I n14:P n14:V n14:Z
n3:aktivity
I, P(GA301/08/1649), P(NS10287), V, Z(AV0Z50380511)
n3:cisloPeriodika
2
n3:dodaniDat
n5:2014
n3:domaciTvurceVysledku
n16:3291464 n16:9013431 n16:9022643
n3:druhVysledku
n13:J
n3:duvernostUdaju
n18:S
n3:entitaPredkladatele
n19:predkladatel
n3:idSjednocenehoVysledku
103481
n3:idVysledku
RIV/68378050:_____/13:00398210
n3:jazykVysledku
n10:eng
n3:klicovaSlova
roscovitine; TRAIL; synergism; apoptosis; leukemia; lymphoma
n3:klicoveSlovo
n6:TRAIL n6:synergism n6:apoptosis n6:leukemia n6:roscovitine n6:lymphoma
n3:kodStatuVydavatele
GB - Spojené království Velké Británie a Severního Irska
n3:kontrolniKodProRIV
[6A4478DD35E9]
n3:nazevZdroje
Leukemia & Lymphoma
n3:obor
n20:EB
n3:pocetDomacichTvurcuVysledku
3
n3:pocetTvurcuVysledku
14
n3:projekt
n4:NS10287 n4:GA301%2F08%2F1649
n3:rokUplatneniVysledku
n5:2013
n3:svazekPeriodika
54
n3:tvurceVysledku
Ludvíková, Z. Strnad, Miroslav Ivánek, R. Molinsky, J. Klánová, M. Klener, P. Nečas, E. Gasova, Z. Koc, Michal Beranová, Lenka Trněný, M. Anděra, Ladislav Bohmova, M. Živný, J.
n3:wos
000313285400027
n3:zamer
n17:AV0Z50380511
s:issn
1042-8194
s:numberOfPages
9
n15:doi
10.3109/10428194.2012.710331