Inhibition of Notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy
Inhibition of Notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy
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DOI：
10.1182/blood-2007-07-102632
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发表时间：
2008-02-15
期刊：
影响因子：
20.3
通讯作者：
Gabrilovich, Dmitry I.
中科院分区：
文献类型：
--
作者：
Nefedova, Yulia;Sullivan, Daniel M.;Gabrilovich, Dmitry I.
耐药仍然是多发性骨髓瘤患者治疗中的一个关键问题。最近的研究已经确定Notch信号在骨髓基质介导的骨髓瘤细胞保护中起主要作用，使其免受药物诱导的新生细胞凋亡。在这里，我们研究了Notch信号的药物抑制是否会影响骨髓瘤细胞的活力及其对化疗的敏感性。单独使用γ -分泌酶抑制剂（GSI）通过特异性抑制Notch信号传导诱导骨髓瘤细胞凋亡。在对骨髓瘤细胞系和原发性骨髓瘤细胞有毒的浓度下，GSI不影响正常骨髓或外周血单个核细胞。GSI治疗可阻止骨髓基质介导的骨髓瘤细胞对药物诱导的凋亡的保护。GSI的细胞毒作用是通过hes1和凋亡前蛋白Noxa的上调介导的。异种移植和SCID-hu多发性骨髓瘤模型的体内实验表明，GSI具有明显的抗肿瘤作用。此外，GSI显著改善了化疗药物阿霉素和美法兰的细胞毒性。因此，本研究表明，抑制Notch信号可以阻止脑卒中介导的耐药，并使骨髓瘤细胞对化疗敏感。这可能为多发性骨髓瘤的治疗干预提供了一种有希望的方法。
Drug resistance remains a critical problem in the treatment of patients with multiple myeloma. Recent studies have determined that Notch signaling plays a major role in bone marrow (BM) stroma-mediated protection of myeloma cells from de novo drug-induced apoptosis. Here, we investigated whether pharmacologic inhibition of Notch signaling could affect the viability of myeloma cells and their sensitivity to chemotherapy. Treatment with a gamma-secretase inhibitor (GSI) alone induced apoptosis of myeloma cells via specific inhibition of Notch signaling. At concentrations toxic for myeloma cell lines and primary myeloma cells, GSI did not affect normal BM or peripheral blood mononuclear cells. Treatment with GSI prevented BM stroma-mediated protection of myeloma cells from drug-induced apoptosis. The cytotoxic effect of GSI was mediated via Hes-1 and up-regulation of the proapoptotic protein Noxa. In vivo experiments using xenograft and SCID-hu models of multiple myeloma demonstrated substantial anti-tumor effect of GSI. In addition, GSI significantly improved the cytotoxicity of the chemotherapeutic drugs doxorubicin and melphalan. Thus, this study demonstrates that inhibition of Notch signaling prevents BM-mediated drug resistance and sensitizes myeloma cells to chemotherapy. This may represent a promising approach for therapeutic intervention in multiple myeloma.