Université de Lyon, Lyon, France.
Clin Cancer Res. 2013 Jul 1;19(13):3556-66. doi: 10.1158/1078-0432.CCR-12-3134. Epub 2013 May 14.
Multiple myeloma is a clonal plasma cell disorder in which growth and proliferation are linked to a variety of growth factors, including insulin-like growth factor type I (IGF-I). Bortezomib, the first-in-class proteasome inhibitor, has displayed significant antitumor activity in multiple myeloma.
We analyzed the impact of IGF-I combined with proteasome inhibitors on multiple myeloma cell lines in vivo and in vitro as well as on fresh human myeloma cells.
Our study shows that IGF-I enhances the cytotoxic effect of proteasome inhibitors against myeloma cells. The effect of bortezomib on the content of proapoptotic proteins such as Bax, Bad, Bak, and BimS and antiapoptotic proteins such as Bcl-2, Bcl-XL, XIAP, Bfl-1, and survivin was enhanced by IGF-I. The addition of IGF-I to bortezomib had a minor effect on NF-κB signaling in MM.1S cells while strongly enhancing reticulum stress. This resulted in an unfolded protein response (UPR), which was required for the potentiating effect of IGF-I on bortezomib cytotoxicity as shown by siRNA-mediated inhibition of GADD153 expression.
These results suggest that the high baseline level of protein synthesis in myeloma can be exploited therapeutically by combining proteasome inhibitors with IGF-I, which possesses a "priming" effect on myeloma cells for this family of compounds.
多发性骨髓瘤是一种克隆性浆细胞疾病，其生长和增殖与多种生长因子有关，包括胰岛素样生长因子 I 型（IGF-I）。硼替佐米是首个蛋白酶体抑制剂，在多发性骨髓瘤中显示出显著的抗肿瘤活性。
我们分析了 IGF-I 与蛋白酶体抑制剂联合对多发性骨髓瘤细胞系体内和体外以及新鲜人骨髓瘤细胞的影响。
我们的研究表明，IGF-I 增强了蛋白酶体抑制剂对骨髓瘤细胞的细胞毒性作用。IGF-I 增强了硼替佐米对促凋亡蛋白如 Bax、Bad、Bak 和 BimS 以及抗凋亡蛋白如 Bcl-2、Bcl-XL、XIAP、Bfl-1 和 survivin 的含量的影响。IGF-I 对 MM.1S 细胞中 NF-κB 信号的影响较小，而强烈增强内质网应激。这导致未折叠蛋白反应（UPR），这是 IGF-I 增强硼替佐米细胞毒性的增强作用所必需的，如通过 GADD153 表达的 siRNA 介导抑制所证明的。
这些结果表明，多发性骨髓瘤中高水平的蛋白质合成可以通过将蛋白酶体抑制剂与 IGF-I 联合治疗来利用，IGF-I 对骨髓瘤细胞具有“启动”作用，使其对这类化合物敏感。
