抑制 MEK/ERK1/2 可增强淋巴瘤细胞对索拉非尼诱导的细胞凋亡的敏感性。
Inhibition of MEK/ERK1/2 sensitizes lymphoma cells to sorafenib-induced apoptosis.
机构信息
Department of Medicine, Institute of Molecular Medicine and the Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States.
出版信息
Leuk Res. 2010 Mar;34(3):379-86. doi: 10.1016/j.leukres.2009.07.013. Epub 2010 Feb 1.
Abstract
Interactions between the multi-kinase inhibitor sorafenib and MEK1/2 inhibitors were investigated in DLBCL cells. Sorafenib (3-10 microM) 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 microM 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.
摘要
多激酶抑制剂索拉非尼与 MEK1/2 抑制剂的相互作用在弥漫性大 B 细胞淋巴瘤细胞中进行了研究。索拉非尼（3-10 μM）可诱导多种 GC 和 ABC 淋巴瘤细胞凋亡。出乎意料的是，索拉非尼不会导致持续的 ERK1/2 失活，并且在 SUDHL-6 和 -16 细胞中触发 ERK1/2 激活。边缘毒性的 MEK1/2 抑制剂浓度（5 μM PD184352）可消除索拉非尼处理细胞中的 ERK1/2 激活，并协同增强细胞凋亡。MEK1 shRNA 转染也显著增加了索拉非尼介导的致死性。索拉非尼/PD184352 联合给药可加速 Mcl-1 的下调，而不会上调 Bim(EL)。最后，异位 Mcl-1 表达减弱了索拉非尼/PD184352 介导的细胞凋亡。总之，这些发现为通过 MEK1/2 抑制剂增强索拉非尼抗淋巴瘤活性提供了理论基础。
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