Effective impairment of myeloma cells and their progenitors by hyperthermia.
Effective impairment of myeloma cells and their progenitors by hyperthermia.
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DOI：
10.18632/oncotarget.23121
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发表时间：
2018-02-13
期刊：
影响因子：
--
通讯作者：
Abe M
中科院分区：
文献类型：
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作者：
Miki H;Nakamura S;Oda A;Tenshin H;Teramachi J;Hiasa M;Bat-Erdene A;Maeda Y;Oura M;Takahashi M;Iwasa M;Harada T;Fujii S;Kurahashi K;Yoshida S;Kagawa K;Endo I;Aihara K;Ikuo M;Itoh K;Hayashi K;Nakamura M;Abe M
多发性骨髓瘤（MM）仍然无法治愈，MM起始细胞或MM祖细胞被认为是通过其耐药性导致疾病复发的原因。为了提高MM的治疗效果，我们最近开发了新型超顺磁性纳米颗粒，其选择性地在MM肿瘤中积聚并通过磁共振产生的热量将其清除。本研究旨在阐明热疗对MM细胞及其祖细胞的治疗作用。43°C下的热处理时间依赖性地诱导MM细胞死亡。治疗上调内质网（ER）应激介质，ATF 4和CHOP，同时降低Pim-2，IRF 4，c-Myc和Mcl-1的蛋白水平。与蛋白酶体抑制剂硼替佐米组合进一步增强ER应激以增强MM细胞死亡。Pim抑制剂SMI-16 a还增强了Pim-2驱动的存活因子IRF 4和c-Myc与热处理组合的减少。热处理几乎完全根除了RPMI 8226和KMS-11细胞中的“侧群”部分，并抑制了它们的克隆形成能力，如通过SCID小鼠中的体外集落形成和致瘤能力所确定的。这些结果共同表明，高温能够损害MM细胞的克隆形成耐药部分，并增强其对化疗药物的敏感性。
Multiple myeloma (MM) remains incurable, and MM-initiating cells or MM progenitors are considered to contribute to disease relapse through their drug-resistant nature. In order to improve the therapeutic efficacy for MM, we recently developed novel superparamagnetic nanoparticles which selectively accumulate in MM tumors and extirpate them by heat generated with magnetic resonance. We here aimed to clarify the therapeutic effects on MM cells and their progenitors by hyperthermia. Heat treatment at 43°C time-dependently induced MM cell death. The treatment upregulated endoplasmic reticulum (ER) stress mediators, ATF4 and CHOP, while reducing the protein levels of Pim-2, IRF4, c-Myc and Mcl-1. Combination with the proteasome inhibitor bortezomib further enhanced ER stress to potentiate MM cell death. The Pim inhibitor SMI-16a also enhanced the reduction of the Pim-2-driven survival factors, IRF4 and c-Myc, in combination with the heat treatment. The heat treatment almost completely eradicated “side population” fractions in RPMI8226 and KMS-11 cells and suppressed their clonogenic capacity as determined by in vitro colony formation and tumorigenic capacity in SCID mice. These results collectively demonstrated that hyperthermia is able to impair clonogenic drug-resistant fractions of MM cells and enhance their susceptibility to chemotherapeutic drugs.