Iron Causes Lipid Oxidation and Inhibits Proteasome Function in Multiple Myeloma Cells: A Proof of Concept for Novel Combination Therapies
Iron Causes Lipid Oxidation and Inhibits Proteasome Function in Multiple Myeloma Cells: A Proof of Concept for Novel Combination Therapies
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DOI：
10.3390/cancers12040970
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发表时间：
2020-04-01
期刊：
影响因子：
5.2
通讯作者：
Campanella, Alessandro
中科院分区：
文献类型：
--
作者：
Bordini, Jessica;Morisi, Federica;Campanella, Alessandro
适应输入铁增殖使癌细胞对铁毒性潜在敏感。铁负荷损害多发性骨髓瘤（MM）细胞增殖，并增加蛋白酶体抑制剂硼替佐米的疗效。在这里，我们定义了MM.1S、U266、H929和OPM-2 MM细胞系中铁毒性的机制，并在使用Vk*MYC小鼠作为MM模型的临床前研究中验证了该策略。高剂量的柠檬酸铁铵在所有测试的细胞系中引发细胞死亡，增加丙二醛水平，脂质过氧化的副产物和铁凋亡指数。此外，铁暴露导致剂量依赖性的积累的多聚泛素化蛋白在高度铁敏感的MM. 1 S和H929细胞，这表明蛋白酶体的工作量有助于铁的敏感性。因此，高铁浓度抑制蛋白酶体糜蛋白酶样活性的26 S颗粒和MM细胞提取物在体外。在所有MM细胞中，硼替佐米-铁组合诱导持续脂质损伤，加剧硼替佐米诱导的多聚泛素化蛋白积聚，并比单独治疗更有效地触发细胞死亡。在Vk*MYC小鼠中，在硼替佐米-美法仑-泼尼松（VMP）方案中加入右旋糖酐铁或羧基麦芽糖铁可增加治疗反应并延长缓解期，而不会引起明显毒性。我们的结论是，铁负荷干扰氧化还原和蛋白质稳态，可以利用设计新的组合策略，包括铁补充剂，以增加目前的MM治疗的疗效的属性。
Adaptation to import iron for proliferation makes cancer cells potentially sensitive to iron toxicity. Iron loading impairs multiple myeloma (MM) cell proliferation and increases the efficacy of the proteasome inhibitor bortezomib. Here, we defined the mechanisms of iron toxicity in MM.1S, U266, H929, and OPM-2 MM cell lines, and validated this strategy in preclinical studies using Vk*MYC mice as MM model. High-dose ferric ammonium citrate triggered cell death in all cell lines tested, increasing malondialdehyde levels, the by-product of lipid peroxidation and index of ferroptosis. In addition, iron exposure caused dose-dependent accumulation of polyubiquitinated proteins in highly iron-sensitive MM.1S and H929 cells, suggesting that proteasome workload contributes to iron sensitivity. Accordingly, high iron concentrations inhibited the proteasomal chymotrypsin-like activity of 26S particles and of MM cellular extracts in vitro. In all MM cells, bortezomib-iron combination induced persistent lipid damage, exacerbated bortezomib-induced polyubiquitinated proteins accumulation, and triggered cell death more efficiently than individual treatments. In Vk*MYC mice, addition of iron dextran or ferric carboxymaltose to the bortezomib-melphalan-prednisone (VMP) regimen increased the therapeutic response and prolonged remission without causing evident toxicity. We conclude that iron loading interferes both with redox and protein homeostasis, a property that can be exploited to design novel combination strategies including iron supplementation, to increase the efficacy of current MM therapies.