Dihydroartemisinin Induces Growth Arrest and Overcomes Dexamethasone Resistance in Multiple Myeloma
Dihydroartemisinin Induces Growth Arrest and Overcomes Dexamethasone Resistance in Multiple Myeloma
复制标题
双氢青蒿素诱导多发性骨髓瘤生长停滞并克服地塞米松耐药性
DOI：
10.3389/fonc.2020.00767
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发表时间：
2020-05-15
影响因子：
4.7
通讯作者：
Yang, Ye
中科院分区：
文献类型：
--
作者：
Chen, Ying;Li, Rui;Yang, Ye
用于治疗疟疾的青蒿素（ART）的发现获得了2015年诺贝尔医学奖，这激发了ART用于治疗包括癌症在内的其他疾病的重新发现和发展。在这项研究中，我们研究了ART和双氢青蒿素（DHA）对多发性骨髓瘤（MM）细胞（包括原代MM细胞）和5 TMM 3VT小鼠模型的潜在治疗作用。体外和体内实验均表明，DHA可能是一种更有前途的抗MM药物，与ART相比，其疗效显著提高。机制分析表明，DHA通过与亚铁离子（Fe 2+）和氧相互作用产生活性氧（ROS）来激活线粒体凋亡途径。有趣的是，DHA可以逆转MM中由地塞米松（Dexa）诱导的B细胞淋巴瘤2（Bcl-2）蛋白（一种典型的线粒体凋亡标志物）的上调表达。我们进一步证明，DHA治疗可以克服Dexa抗性并增强Dexa在MM中的疗效。此外，DHA与Dexa联合导致ROS产生增加和细胞色素C从线粒体向细胞质的转运，导致线粒体膜电位的改变和半胱天冬酶介导的细胞凋亡。总之，我们的研究表明，DHA在MM治疗中上级优于ART，并在体外和体内克服了Dexa耐药性，为MM治疗提供了一种有前景的治疗策略。
The discovery of artemisinin (ART) for malaria treatment won the 2015 Nobel Prize in Medicine, which inspired the rediscovery and development of ART for the treatment of other diseases including cancer. In this study, we investigated the potential therapeutic effect of ART and dihydroartemisinin (DHA) on multiple myeloma (MM) cells including primary MM cells and in 5TMM3VT mouse model. Both in vitro and in vivo experiments showed that DHA might be a more promising anti-MM agent with significantly improved efficacy compared to ART. Mechanistic analyses suggested that DHA activated the mitochondrial apoptotic pathway by interacting with ferrous (Fe2+) ions and oxygen to produce reactive oxygen species (ROS). Intriguingly, DHA could reverse the upregulated expression of B-cell lymphoma 2 (Bcl-2) protein, a typical mitochondrial apoptotic marker, induced by dexamethasone (Dexa) in MM. We further demonstrated that DHA treatment could overcome Dexa resistance and enhance Dexa efficacy in MM. Additionally, DHA combined with Dexa resulted in increased ROS production and cytochrome C translocation from the mitochondria to the cytoplasm, resulting in alterations to the mitochondrial membrane potential and caspase-mediated apoptosis. In summary, our study demonstrated that DHA was superior to ART in MM treatment and overcame Dexa resistance both in vitro and in vivo, providing a promising therapeutic strategy for MM therapy.