Inhibition of autophagy with chloroquine potentiates carfilzomib-induced apoptosis in myeloma cells in vitro and in vivo
Inhibition of autophagy with chloroquine potentiates carfilzomib-induced apoptosis in myeloma cells in vitro and in vivo
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DOI：
10.1016/j.canlet.2016.08.019
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发表时间：
2016-11-01
期刊：
影响因子：
9.7
通讯作者：
Naval, Javier
中科院分区：
文献类型：
--
作者：
Jarauta, Vidal;Jaime, Paula;Naval, Javier
蛋白酶体抑制剂硼替佐米现在是多发性骨髓瘤（MM）联合治疗的基石。卡非佐米是第二代抑制剂，与硼替佐米相比，在联合治疗方案中显示出实质性获益。在这里，我们详细分析了由卡非佐米诱导的细胞死亡的机制及其与自噬的串扰，并将结果应用于小鼠模型中MM的体内治疗。卡非佐米主要通过内源性途径诱导细胞凋亡，通过上调Puma和Noxa蛋白，随后Puma、Noxa和Bim与Bax以及Noxa与巴克相互作用。卡非佐米也增加了自噬体的形成，但随着凋亡的进展，自噬被破坏，可能是由于Beclin 1和p62失活。氯喹，阻断自噬，在体外和体内强烈增强细胞凋亡。因此，在小鼠异种移植模型中，卡非佐米加氯喹的联合治疗对MM的治疗非常有效。氯喹还增强了经历凋亡的MM细胞中卡非佐米诱导的钙网蛋白暴露，增加了卡非佐米的免疫原性能力。这些结果支持将卡非佐米与氯喹联合使用以改善MM治疗的试验设计。(C)2016爱思唯尔爱尔兰有限公司版权所有。
The proteasome inhibitor bortezomib is now the cornerstone of combination therapy of multiple myeloma (MM). Carfilzomib, a second-generation inhibitor, has shown a substantial benefit vs bortezomib in combination regimes. Here we have analyzed in detail the mechanism of cell death induced by carfilzomib and its crosstalk with autophagy and applied the results to the in vivo treatment of MM in a mouse model. Carfilzomib induced apoptosis essentially by the intrinsic pathway, through the up-regulation of Puma and Noxa proteins followed by the interaction of Puma, Noxa and Bim with Bax and of Noxa with Bak. Carfilzomib also produces an increase in the formation of autophagosomes but, as apoptosis progresses, autophagy is disrupted, probably owing to Beclin 1 and p62 inactivation. Cotreatment with chloroquine, which blocks autophagy, strongly potentiated apoptosis in vitro and in vivo. Accordingly, combination therapy with carfilzomib plus chloroquine was highly effective in the treatment of MM in a mouse xenograft model. Chloroquine also enhanced carfilzomib-induced calreticulin exposure in MM cells undergoing apoptosis, increasing the immunogenic ability of carfilzomib. These results support design of trials combining carfilzomib with chloroquine to improve MM therapy. (C) 2016 Elsevier Ireland Ltd. All rights reserved.