Inhibition of MEK/ERK1/2 sensitizes lymphoma cells to sorafenib-induced apoptosis

被引：22

作者：

Nguyen, Tri K. ^{[2
]}

Jordan, Nicholas ^{[2
]}

Friedberg, Jonathan ^{[5
]}

Fisher, Richard I. ^{[5
]}

Dent, Paul ^{[2
,3
]}

Grant, Steven ^{[1
,2
,3
,4
]}

机构：

[1] Virginia Commonwealth Univ, Div Hematol Oncol, Goodwin Res Lab, Inst Mol Med,Dept Med, Richmond, VA 23298 USA

[2] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA 23298 USA

[3] Virginia Commonwealth Univ, Inst Mol Med, Dept Biochem, Richmond, VA 23298 USA

[4] Virginia Commonwealth Univ, Inst Mol Med, Dept Pharmacol, Richmond, VA 23298 USA

[5] Univ Rochester, James P Wilmot Canc Ctr, Rochester, NY 14627 USA

来源：

LEUKEMIA RESEARCH | 2010年 / 34卷 / 03期

基金：

美国国家卫生研究院;

关键词：

Lymphoma; Sorafenib; PD184352; MEK1/2/ERK1/2; Mcl-1; HUMAN-LEUKEMIA-CELLS; KAPPA-B ACTIVITY; SIGNALING PATHWAY; RAS/RAF/MEK/ERK PATHWAY; MULTIKINASE INHIBITOR; ELDERLY-PATIENTS; DOWN-REGULATION; MCL-1; KINASE; EXPRESSION;

D O I：

10.1016/j.leukres.2009.07.013

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Interactions between the multi-kinase inhibitor sorafenib and MEK1/2 inhibitors were investigated in DLBCL cells. Sorafenib (3-10 mu M) triggered apoptosis in multiple GC and ABC lymphoma cells. Unexpectedly, sorafenib did not cause sustained ERK1/2 inactivation, and in SUDHL-6 and -16 cells, triggered ERK1/2 activation. Marginally toxic MEK1/2 inhibitor concentrations (5 mu M PD184352) abrogated ERK1/2 activation in sorafenib-treated cells and synergistically potentiated apoptosis. MEK1 shRNA transfection also significantly increased sorafenib-mediated lethality. Sorafenib/PD184352 co-administration accelerated Mcl-1 down-regulation without up-regulating Bim(EL). Finally, ectopic Mcl-1 expression attenuated sorafenib/PD184352-mediated apoptosis. Together, these findings provide a theoretical basis for potentiating sorafenib anti-lymphoma activity by MEK1/2 inhibitors. (C) 2010 Published by Elsevier Ltd.

引用

页码：379 / 386

页数：8

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