Pevonedistat, a NEDD8-activating enzyme inhibitor, is active in mantle cell lymphoma and enhances rituximab activity in vivo

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064165%3A_____%2F16%3A10327537" target="_blank" >RIV/00064165:_____/16:10327537 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11110/16:10327537

Výsledek na webu

<a href="http://dx.doi.org/10.1182/blood-2015-04-640920" target="_blank" >http://dx.doi.org/10.1182/blood-2015-04-640920</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1182/blood-2015-04-640920" target="_blank" >10.1182/blood-2015-04-640920</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Pevonedistat, a NEDD8-activating enzyme inhibitor, is active in mantle cell lymphoma and enhances rituximab activity in vivo

Popis výsledku v původním jazyce

Mantle cell lymphoma(MCL) is characterized by an aggressive clinical course and inevitable development of refractory disease, stressing the need to develop alternative therapeutic strategies. To this end, we evaluated pevonedistat (MLN4924), a novel potent and selective NEDD8-activating enzyme inhibitor in a panel of MCL cell lines, primary MCL tumor cells, and 2 distinct murine models of human MCL. Pevonedistat exposure resulted in a dose-, time-, and caspase-dependent cell death in the majority of the MCL cell lines and primary tumor cells tested. Of interest, in the MCL cell lines with lower half-maximal inhibitory concentration (0.1-0.5 mu M), pevonedistat induced G1-phase cell cycle arrest, down-regulation of Bcl-xL levels, decreased nuclear factor (NF)-kappa B activity, and apoptosis. In addition, pevonedistat exhibited additive/synergistic effects when combined with cytarabine, bendamustine, or rituximab. In vivo, as a single agent, pevonedistat prolonged the survival of 2 MCL-bearing mouse models when compared with controls. Pevonedistat in combination with rituximab led to improved survival compared with rituximab or pevonedistat monotherapy. Our data suggest that pevonedistat has significant activity in MCL preclinical models, possibly related to effects on NF-kappa B activity, Bcl-xL downregulation, and G1 cell cycle arrest. Our findings support further investigation of pevonedistat with or without rituximab in the treatment of MCL.

Název v anglickém jazyce

Pevonedistat, a NEDD8-activating enzyme inhibitor, is active in mantle cell lymphoma and enhances rituximab activity in vivo

Popis výsledku anglicky

Mantle cell lymphoma(MCL) is characterized by an aggressive clinical course and inevitable development of refractory disease, stressing the need to develop alternative therapeutic strategies. To this end, we evaluated pevonedistat (MLN4924), a novel potent and selective NEDD8-activating enzyme inhibitor in a panel of MCL cell lines, primary MCL tumor cells, and 2 distinct murine models of human MCL. Pevonedistat exposure resulted in a dose-, time-, and caspase-dependent cell death in the majority of the MCL cell lines and primary tumor cells tested. Of interest, in the MCL cell lines with lower half-maximal inhibitory concentration (0.1-0.5 mu M), pevonedistat induced G1-phase cell cycle arrest, down-regulation of Bcl-xL levels, decreased nuclear factor (NF)-kappa B activity, and apoptosis. In addition, pevonedistat exhibited additive/synergistic effects when combined with cytarabine, bendamustine, or rituximab. In vivo, as a single agent, pevonedistat prolonged the survival of 2 MCL-bearing mouse models when compared with controls. Pevonedistat in combination with rituximab led to improved survival compared with rituximab or pevonedistat monotherapy. Our data suggest that pevonedistat has significant activity in MCL preclinical models, possibly related to effects on NF-kappa B activity, Bcl-xL downregulation, and G1 cell cycle arrest. Our findings support further investigation of pevonedistat with or without rituximab in the treatment of MCL.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

FD - Onkologie a hematologie

OECD FORD obor

—

Projekt

<a href="/cs/project/NT13201" target="_blank" >NT13201: Role angiogeneze v přežití, růstu, šíření a terapeutické odpovědi lymfomu z plášťových buněk (Mantle Cell Lymphoma, MCL)</a><br>

Návaznosti

V - Vyzkumna aktivita podporovana z jinych verejnych zdroju

Rok uplatnění

2016

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Blood

ISSN

0006-4971

e-ISSN

—

Svazek periodika

127

Číslo periodika v rámci svazku

9

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

10

Strana od-do

1128-1137

Kód UT WoS článku

000373401700013

EID výsledku v databázi Scopus

2-s2.0-84960469722