Combined inhibition of Notch signaling and Bcl-2/Bcl-xL results in synergistic antimyeloma effect.
Combined inhibition of Notch signaling and Bcl-2/Bcl-xL results in synergistic antimyeloma effect.
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DOI：
10.1158/1535-7163.mct-10-0372
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发表时间：
2010-12
影响因子：
5.7
通讯作者：
Nefedova Y
中科院分区：
文献类型：
--
作者：
Li M;Chen F;Clifton N;Sullivan DM;Dalton WS;Gabrilovich DI;Nefedova Y
通过受体/转录调节因子Notch途径的信号传导在肿瘤细胞存活中起重要作用。最近的研究表明，用γ-分泌酶抑制剂（GSI）药理学抑制Notch途径通过上调促凋亡蛋白Noxa诱导多发性骨髓瘤（MM）细胞凋亡。ABT-737是一种新的BH 3模拟物，可阻断Bcl-2和Bcl-xL并诱导MM细胞凋亡。在这里，我们研究了Notch信号的抑制是否可以增强ABT-737的促凋亡作用。通过添加Notch抑制剂，ABT-737对MM细胞系或原代细胞的抗骨髓瘤作用显著增加。GSI+ABT-737组合的协同效应通过巴克和Bax的活化以及细胞色素c的释放介导。虽然对MM细胞有毒，但GSI和ABT-737的组合不影响从健康供体分离的外周血单核细胞的存活。使用MM的异种移植物和SCID-hu模型的体内实验证明，与单独的Notch或Bcl-2/Bcl-xL抑制剂的作用相比，GSI/ABT-737组合具有显著的抗肿瘤作用。因此，这种药物组合可能对MM患者有治疗益处。
Signaling through the receptor/transcriptional regulator Notch pathway plays an important role in tumor cell survival. Recent studies have demonstrated that pharmacological inhibition of the Notch pathway with γ-secretase inhibitor (GSI) induces apoptosis of multiple myeloma (MM) cells via up-regulation of the proapoptotic protein Noxa. ABT-737, a novel BH3 mimetic, was shown to block Bcl-2 and Bcl-xL and induce MM cell apoptosis. Here we investigated whether the inhibition of Notch signaling could enhance the proapoptotic effect of ABT-737. The anti-myeloma effect of ABT-737 on MM cell lines or primary cells was substantially increased by the addition of Notch inhibitor. The synergistic effect of the GSI+ABT-737 combination was mediated by activation of Bak and Bax and release of cytochrome c. While toxic for MM cells, the combination of GSI and ABT-737 did not affect survival of peripheral blood mononuclear cells isolated from healthy donors. In vivo experiments using xenograft and SCID-hu models of MM demonstrated a significant antitumor effect of the GSI/ABT-737 combination as compared to the effect of Notch or Bcl-2/Bcl-xL inhibitors alone. Thus, this drug combination may be therapeutically beneficial for patients with MM.