Nefedova Yulia, Sullivan Daniel M, Bolick Sophia C, Dalton William S, Gabrilovich Dmitry I
H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa 33612, USA.
Blood. 2008 Feb 15;111(4):2220-9. doi: 10.1182/blood-2007-07-102632. Epub 2007 Nov 26.
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 antitumor 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.
耐药性仍是多发性骨髓瘤患者治疗中的一个关键问题。最近的研究已确定，Notch信号通路在骨髓（BM）基质介导的骨髓瘤细胞免受药物诱导的凋亡中起主要作用。在此，我们研究了Notch信号通路的药理学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）进行治疗，通过特异性抑制Notch信号通路诱导骨髓瘤细胞凋亡。在对骨髓瘤细胞系和原代骨髓瘤细胞有毒性的浓度下，GSI不影响正常骨髓或外周血单个核细胞。GSI治疗可防止BM基质介导的骨髓瘤细胞免受药物诱导的凋亡。GSI的细胞毒性作用是通过Hes-1和促凋亡蛋白Noxa的上调介导的。使用多发性骨髓瘤的异种移植和SCID-hu模型进行的体内实验证明了GSI具有显著的抗肿瘤作用。此外，GSI显著提高了化疗药物阿霉素和美法仑的细胞毒性。因此，本研究表明，抑制Notch信号通路可防止BM介导的耐药性，并使骨髓瘤细胞对化疗敏感。这可能是一种有前景的多发性骨髓瘤治疗干预方法。
