Hydroxychloroquine potentiates carfilzomib toxicity towards myeloma cells.
Hydroxychloroquine potentiates carfilzomib toxicity towards myeloma cells.
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DOI：
10.18632/oncotarget.12226
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发表时间：
2016-10-25
期刊：
影响因子：
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通讯作者：
Sundan A
中科院分区：
文献类型：
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作者：
Baranowska K;Misund K;Starheim KK;Holien T;Johansson I;Darvekar S;Buene G;Waage A;Bjørkøy G;Sundan A
细胞通过蛋白酶体降解蛋白质，蛋白酶体在临床上被例如硼替佐米或卡非佐米靶向，或者通过形成自噬体和溶酶体降解，溶酶体降解可以被羟氯喹（HCQ）抑制。多发性骨髓瘤是一种独特的癌症，因为蛋白酶体抑制剂具有良好的临床效果。然而，一些多发性骨髓瘤患者显示出对治疗的内在抗性，并且大多数患者随着时间的推移获得抗性。我们假设同时靶向蛋白降解的两个臂可能是改善多发性骨髓瘤治疗的一种方法。在这里，我们测试了溶酶体抑制剂HCQ和临床相关的蛋白酶体抑制剂对骨髓瘤细胞系和原代细胞的联合作用。卡非佐米和硼替佐米均诱导骨髓瘤细胞中含有免疫球蛋白的聚集体。HCQ显著增强了卡非佐米在两种细胞系和原代骨髓瘤细胞中的作用。相比之下，HCQ对硼替佐米的毒性影响很小或没有影响。此外，适应耐受高水平卡非佐米的细胞可通过与HCQ共处理而对药物重新致敏。因此，我们发现抑制溶酶体降解可以克服卡非佐米耐药性，这表明骨髓瘤细胞中自噬的作用依赖于蛋白酶体抑制剂的类型。总之，在多发性骨髓瘤的治疗中应尝试联合收割机HCQ与卡非佐米的联合应用。
Cells degrade proteins either by proteasomes that clinically are targeted by for example bortezomib or carfilzomib, or by formation of autophagosomes and lysosomal degradation that can be inhibited by hydroxychloroquine (HCQ). Multiple myeloma is unique among cancers because proteasomal inhibition has good clinical effects. However, some multiple myeloma patients display intrinsic resistance to the treatment and most patients acquire resistance over time. We hypothesized that simultaneous targeting both arms of protein degradation could be a way to improve treatment of multiple myeloma. Here we tested the combined effects of the lysosomal inhibitor HCQ and clinically relevant proteasome inhibitors on myeloma cell lines and primary cells. Carfilzomib and bortezomib both induced immunoglobulin-containing aggregates in myeloma cells. HCQ significantly potentiated the effect of carfilzomib in both cell lines and in primary myeloma cells. In contrast, HCQ had little or no effects on the toxicity of bortezomib. Furthermore, cells adapted to tolerate high levels of carfilzomib could be re-sensitized to the drug by co-treatment with HCQ. Thus, we show that inhibition of lysosomal degradation can overcome carfilzomib resistance, suggesting that the role of autophagy in myeloma cells is dependent on type of proteasome inhibitor. In conclusion, attempts should be made to combine HCQ with carfilzomib in the treatment of multiple myeloma.