Autophagy inhibition enhances isobavachalcone-induced cell death in multiple myeloma cells.
Autophagy inhibition enhances isobavachalcone-induced cell death in multiple myeloma cells.
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DOI：
10.3892/ijmm.2012.1066
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发表时间：
2012-10
影响因子：
5.4
通讯作者：
Shan Zhao;Chunmin Ma;Chuan-Xu Liu;Wei Wei-Wei;Yun Sun;Hua Yan;Yingli Wu
中科院分区：
文献类型：
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作者：
Shan Zhao;Chunmin Ma;Chuan-Xu Liu;Wei Wei-Wei;Yun Sun;Hua Yan;Yingli Wu
尽管治疗药物最近取得了进展，多发性骨髓瘤仍然是一种无法治愈的疾病。因此，迫切需要更有效的治疗方法。在这项研究中，我们发现异巴伐查尔酮 (IBC)（一种天然查尔酮化合物）可诱导骨髓瘤细胞中与细胞凋亡和自噬相关的细胞死亡。通过敲低 beclin-1 或使用自噬抑制剂（如 3-甲基腺嘌呤、巴弗洛霉素 A 和氯喹）来抑制自噬，可显着增强 IBC 诱导的细胞死亡，Annexin V 阳性细胞数量增加就证明了这一点。此外，我们证明线粒体膜电位的崩溃会导致氯喹和 IBC 诱导的细胞死亡，同时伴随着 caspase-9 和 -3 的激活、聚（ADP-核糖）聚合酶（PARP）的裂解以及蛋白激酶 Cδ（PKCδ）的蛋白水解激活。此外，PKCδ抑制剂rottlerin对PKCδ活化的抑制不仅抑制了PKCδ的活化，而且抑制了氯喹和IBC联合处理诱导的细胞凋亡，表明PKCδ参与了氯喹加IBC诱导的细胞死亡。最后，氯喹和IBC联合使用对正常外周血单个核细胞的活力几乎没有影响。由于氯喹和 IBC 均已被证明对癌细胞具有相对特异性，因此这两种药物在无毒或亚毒浓度下的组合代表了一种有吸引力的骨髓瘤治疗新方案，值得在临床前和临床研究中进行进一步研究。
Despite recent advancements in therapeutic drugs, multiple myeloma remains an incurable disease. Therefore, a more effective treatment is urgently required. In this study, we show that isobavachalcone (IBC), a natural chalcone compound, induces apoptosis- and autophagy-related cell death in myeloma cells. The inhibition of autophagy by knocking down beclin-1 or by using autophagy inhibitors, such as 3-methyladenine, bafilomycin A and chloroquine significantly enhanced IBC-induced cell death, as demonstrated by the increased number of Annexin V-positive cells. Moreover, we demonstrate that the collapse of the mitochondrial membrane potential contributes to chloroquine and IBC-induced cell death, which is accompanied by the activation of caspase-9, and -3, the cleavage of poly (ADP-ribose) polymerase (PARP) and the proteolytic activation of protein kinase Cδ (PKCδ). Furthermore, the inhibition of the activation of PKCδ by rottlerin, an inhibitor of PKCδ, not only suppressed the activation of PKCδ, but also the apoptosis induced by the co-treatment of chloroquine and IBC, indicating the involvement of PKCδ in chloroquine plus IBC-induced cell death. Finally, the combination of chloroquine and IBC had little effect on the viability of normal peripheral blood mononuclear cells. As both chloroquine and IBC have been shown to be relatively specific for cancer cells, the combination of these two agents at non-toxic or sub-toxic concentrations represents an attractive novel regimen for myeloma treatment and warrants further investigation in preclinical and clinical studies.