Proteasome inhibitor bortezomib is one of the most effective drugs currently available for the treatment of multiple myeloma (MM). However, the intrinsic and acquired resistance to bortezomib can limit its effectiveness. The activation of heat shock response has been characterized as a potential resistance mechanism protecting MM cells from bortezomib-induced cell death. In this study, in response to bortezomib therapy, we discovered that HSP70 is one of the most substantially upregulated heat shock proteins. In order to further explore approaches to sensitizing bortezomib-based treatment for MM, we investigated whether targeting HSP70 using a specific inhibitor VER-155008 combined with bortezomib could overcome the acquired resistance in MM. We found that HSP70 inhibitor VER-155008 alone significantly decreased MM cell viability. Moreover, the combination of VER-155008 and bortezomib synergistically induced MM cell apoptosis markedly in vitro. Notably, the combined treatment was found to increase the cleavage of PARP, an early marker of chemotherapy-induced apoptosis. Importantly, the reduction of anti-apoptotic Bcl-2 family member Bcl-2, Bcl-xL, and Mcl-1 and the induction of pro-apoptotic Bcl-2 family member BH3-only protein NOXA and Bim were confirmed to be tightly associated with the synergism. Finally, the ER stress marker CHOP (CCAAT-enhancer binding protein homologous protein), which can cause transcriptional activation of genes involved in cell apoptosis, was markedly induced by both VER-155008 and bortezomib. Taken together, our finding of a strong synergistic interaction between VER-155008 and bortezomib may support for combination therapy in MM patients in the future.

中文翻译：

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VER-155008 阻断 HSP70 可协同增强硼替佐米诱导的多发性骨髓瘤细胞毒性。


蛋白酶体抑制剂硼替佐米是目前治疗多发性骨髓瘤（MM）最有效的药物之一。然而，硼替佐米的内在和获得性耐药性会限制其有效性。热休克反应的激活被认为是保护 MM 细胞免受硼替佐米诱导的细胞死亡的潜在抵抗机制。在这项研究中，针对硼替佐米治疗，我们发现 HSP70 是上调最显着的热休克蛋白之一。为了进一步探索基于硼替佐米的MM治疗增敏方法，我们研究了使用特异性抑制剂VER-155008联合硼替佐米靶向HSP70是否可以克服MM的获得性耐药。我们发现 HSP70 抑制剂 VER-155008 单独显着降低 MM 细胞活力。此外，VER-155008和硼替佐米的组合在体外显着协同诱导MM细胞凋亡。值得注意的是，联合治疗被发现可以增加 PARP 的裂解，PARP 是化疗诱导细胞凋亡的早期标志物。重要的是，抗凋亡 Bcl-2 家族成员 Bcl-2、Bcl-xL 和 Mcl-1 的减少与促凋亡 Bcl-2 家族成员 BH3-only 蛋白 NOXA 和 Bim 的诱导被证实紧密相关与协同作用。最后，VER-155008 和硼替佐米均显着诱导了 ER 应激标记 CHOP（CCAAT 增强子结合蛋白同源蛋白），该标记可引起细胞凋亡相关基因的转录激活。综上所述，我们发现 VER-155008 和硼替佐米之间存在很强的协同相互作用，这可能支持未来多发性骨髓瘤患者的联合治疗。