Disulfiram/copper markedly induced myeloma cell apoptosis through activation of JNK and intrinsic and extrinsic apoptosis pathways
Disulfiram/copper markedly induced myeloma cell apoptosis through activation of JNK and intrinsic and extrinsic apoptosis pathways
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双硫仑/铜通过激活 JNK 以及内在和外在凋亡途径显着诱导骨髓瘤细胞凋亡
DOI：
10.1016/j.biopha.2020.110048
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发表时间：
2020
影响因子：
7.5
通讯作者：
Chengyun Zheng
中科院分区：
文献类型：
--
作者：
Yaqi Xu;Qian Zhou;Xiaoli Feng;Yibo Dai;Yang Jiang;Wen Jiang;Xiaoli Liu;Xiangling Xing;Yongjing Wang;Yihong Ni;Chengyun Zheng
双硫仑（DSF）是FDA批准的抗酒精药物，已经使用了60多年。近年来，已发现DSF/Cu （DSF/Cu）复合物具有抗肿瘤活性。然而，其抗多发性骨髓瘤活性几乎没有被研究过。在本研究中，我们的研究结果表明，DSF/Cu复合物诱导MM细胞和MM原代细胞凋亡。结果表明，DSF/Cu显著诱导MM.1S和RPMI8226细胞的G2/M期细胞周期阻滞。此外，JC-1和Western blot结果显示，DSF/Cu分别破坏了MM细胞的线粒体膜完整性和切割了caspase-8，表明它诱导了外源性和内源性凋亡途径的激活。有趣的是，DSF/Cu诱导的caspase-3激活被一种泛caspase抑制剂Z-VAD-FMK （zVAD）部分阻断，表明在DSF/Cu诱导的骨髓瘤细胞凋亡机制中涉及caspase依赖性和非依赖性途径。此外，在DSF/Cu处理的MM细胞中观察到c-Jun n末端激酶（JNK）信号通路的激活。更重要的是，我们的研究结果表明，与对照组相比，DSF/Cu显著减少了MM小鼠的肿瘤体积，延长了总生存期。综上所述，我们的新发现表明，DSF/Cu在体外和体内都具有强大的抗骨髓瘤活性，这突出了DSF/Cu在骨髓瘤治疗中的宝贵临床潜力。
Disulfiram (DSF) is an FDA approved anti-alcoholism drug in use for more than 60 years. Recently, antitumor activity of the DSF/copper (DSF/Cu) complex has been identified. Its anti-multiple myeloma activity, however, has barely been investigated. In the present study, our results demonstrated that the DSF/Cu complex induced apoptosis of MM cells and MM primary cells. The results indicated that DSF/Cu significantly induced cell cycle arrest at the G2/M phase in MM.1S and RPMI8226 cells. Moreover, JC-1 and Western blot results showed that DSF/Cu disrupted mitochondrial membrane integrity and cleaved caspase-8 in MM cells, respectively, suggesting that it induced activation of extrinsic and intrinsic apoptosis pathways. Interestingly, DSF/Cu induced caspase-3 activation was partly blocked by Z-VAD-FMK (zVAD), a pan-caspase inhibitor, indicating at caspase-dependent and -independent paths involved in DSF/Cu induced myeloma cell apoptosis machinery. Additionally, activation of the c-Jun N-terminal kinase (JNK) signaling pathway was observed in DSF/Cu treated MM cells. More importantly, our results demonstrated that DSF/Cu significantly reduced tumor volumes and prolonged overall survival of MM bearing mice when compared with the controls. Taken together, our novel findings showed that DSF/Cu has potent anti-myeloma activity in vitro and in vivo highlighting valuable clinical potential of DSF/Cu in MM treatment.