Zhang Mingjun, He Jin, Liu Zhiqiang, Lu Yong, Zheng Yuhuan, Li Haiyan, Xu Jingda, Liu Huan, Qian Jianfei, Orlowski Robert Z, Kwak Larry W, Yi Qing, Yang Jing
Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Oncotarget. 2015 Apr 20;6(11):8567-78. doi: 10.18632/oncotarget.3251.
Our previous studies showed that anti-β2M monoclonal antibodies (mAbs) have strong and direct apoptotic effects on multiple myeloma (MM) cells, suggesting that anti-β2M mAbs might be developed as a novel therapeutic agent. In this study, we investigated the anti-MM effects of combination treatment with anti-β2M mAbs and bortezomib (BTZ). Our results showed that anti-β2M mAbs enhanced BTZ-induced apoptosis of MM cell lines and primary MM cells. Combination treatment could also induce apoptosis of BTZ-resistant MM cells, and the enhanced effect depended on the surface expression of β2M on MM cells. BTZ up-regulated the expression of autophagy proteins, whereas combination with anti-β2M mAbs inhibited autophagy. Sequence analysis of the promoter region of beclin 1 identified 3 putative NF-κB-binding sites from -615 to -789 bp. BTZ treatment increased, whereas combination with anti-β2M mAbs reduced, NF-κB transcription activities in MM cells, and combination treatment inhibited NF-κB p65 binding to the beclin 1 promoter. Furthermore, anti-β2M mAbs and BTZ combination treatment had anti-MM activities in an established MM mouse model. Thus, our studies provide new insight and support for the clinical development of an anti-β2M mAb and BTZ combination treatment to overcome BTZ drug resistance and improve MM patient survival.
我们之前的研究表明，抗β2微球蛋白单克隆抗体（mAbs）对多发性骨髓瘤（MM）细胞具有强大且直接的凋亡作用，这表明抗β2微球蛋白单克隆抗体可能被开发为一种新型治疗药物。在本研究中，我们调查了抗β2微球蛋白单克隆抗体与硼替佐米（BTZ）联合治疗的抗MM效果。我们的结果表明，抗β2微球蛋白单克隆抗体增强了BTZ诱导的MM细胞系和原代MM细胞的凋亡。联合治疗还可诱导BTZ耐药MM细胞的凋亡，且增强作用取决于MM细胞表面β2微球蛋白的表达。BTZ上调了自噬蛋白的表达，而与抗β2微球蛋白单克隆抗体联合则抑制自噬。对beclin 1启动子区域的序列分析确定了从-615至-789 bp的3个假定的NF-κB结合位点。BTZ处理增加了MM细胞中的NF-κB转录活性，而与抗β2微球蛋白单克隆抗体联合则降低了该活性，联合治疗抑制了NF-κB p65与beclin 1启动子的结合。此外，抗β2微球蛋白单克隆抗体与BTZ联合治疗在已建立的MM小鼠模型中具有抗MM活性。因此，我们的研究为抗β2微球蛋白单克隆抗体与BTZ联合治疗的临床开发提供了新的见解和支持，以克服BTZ耐药性并提高MM患者的生存率。
