Vorinostat and quinacrine have synergistic effects in T-cell acute lymphoblastic leukemia through reactive oxygen species increase and mitophagy inhibition.
Vorinostat and quinacrine have synergistic effects in T-cell acute lymphoblastic leukemia through reactive oxygen species increase and mitophagy inhibition.
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伏立诺他和奎纳克林通过增加活性氧和抑制线粒体自噬对 T 细胞急性淋巴细胞白血病具有协同作用。
DOI：
10.1038/s41419-018-0679-6
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发表时间：
2018-05-22
影响因子：
9
通讯作者：
Wu Y
中科院分区：
文献类型：
--
作者：
Jing B;Jin J;Xiang R;Liu M;Yang L;Tong Y;Xiao X;Lei H;Liu W;Xu H;Deng J;Zhou L;Wu Y
尽管最近在治疗方面取得了进展，但成人急性T淋巴细胞白血病(T-ALL)的预后很差。迫切需要开发新的方法来抗击这种疾病。伏立诺是一种泛组蛋白脱乙酰酶(HDAC)抑制剂，在多种实体和血液系统恶性肿瘤中发挥着良好的抗癌活性。然而，单一的止涡器治疗效果并不令人满意。在这里，我们证明了喹卡林(QC)，一种具有强大的自噬抑制活性的抗疟疾药物，可以在无毒浓度下协同增强伏立诺诱导的细胞死亡。与单独用药相比，清热解毒胶囊联合伏立诺显著诱导细胞凋亡，破坏线粒体膜电位，降低Mcl-1和Bcl2/Bax比值。有趣的是，QC和涡旋剂的应用导致了线粒体吞噬功能的阻断，反映在K63相关的线粒体蛋白泛素化增加和线粒体侵袭体的形成上。QC加伏立诺能显著提高细胞内的ROS水平。此外，ROS清除剂N-乙酰半胱氨酸(NAC)取消了QC加华力诺诱导的ROS，减少了线粒体蛋白的泛素化，减少了细胞死亡。最后，使用异种移植小鼠模型，我们证明了QC加伏立恒在体内显著抑制细胞增殖和诱导细胞死亡。综上所述，我们的结果表明QC联合伏立诺治疗T细胞急性淋巴细胞白血病可能是一种新的治疗方案，值得在未来进行临床评估。
Despite recent progress in the treatment, the outcome of adult acute T-cell lymphoblastic leukemia (T-ALL) is poor. Development of novel approach to combat this disease is urgently required. Vorinostat, a pan-histone deacetylase (HDAC) inhibitor, exerts promising anticancer activity in a variety of solid and hematologic malignancies. However, the efficacy of vorinostat monotherapy is unsatisfactory. Here, we show that quinacrine (QC), an anti-malaria drug with potent autophagy inhibitory activity, could synergistically enhance vorinostat-induced cell death at a non-toxic concentration. Compared to the single treatment, QC plus vorinostat significantly induced apoptosis, disrupted the mitochondrial transmembrane potential, and decreased Mcl-1 and Bcl-2/Bax ratio. Interestingly, the application of QC plus vorinostat resulted in mitophagy blockade, as reflected by the increase in the K63-linked ubiquitination of mitochondria protein and the formation of mitochondrial aggresomes. QC plus vorinostat markedly increased the reactive oxygen species (ROS) level in cells. Moreover, the ROS scavenger N-acetylcysteine (NAC) abrogated QC plus vorinostat-induced ROS, decreased the ubiquitination of mitochondria proteins, and cell death. Finally, using a xenograft mouse model, we demonstrated that QC plus vorinostat significantly reduced cell proliferation and induced cell death in vivo. Taken together, our results showed that the combination of QC with vorinostat may represent a novel regimen for the treatment of T-cell acute lymphoblastic leukemia, which deserves clinical evaluation in the future.
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影响因子：
12.8
作者：
Eriksson A;Österroos A;Hassan S;Gullbo J;Rickardson L;Jarvius M;Nygren P;Fryknäs M;Höglund M;Larsson R
通讯作者：
Larsson R
影响因子：
6.5
作者：
Ogura M;Ando K;Suzuki T;Ishizawa K;Oh SY;Itoh K;Yamamoto K;Au WY;Tien HF;Matsuno Y;Terauchi T;Yamamoto K;Mori M;Tanaka Y;Shimamoto T;Tobinai K;Kim WS
通讯作者：
Kim WS
影响因子：
2.9
作者：
Liang, Gong-Wen;Lu, Wan-Liang;Zhang, Qiang
通讯作者：
Zhang, Qiang
影响因子：
8.8
作者：
deSouza, PL;Castillo, M;Myers, CE
通讯作者：
Myers, CE
影响因子：
--
作者：
Song P;Ye L;Fan J;Li Y;Zeng X;Wang Z;Wang S;Zhang G;Yang P;Cao Z;Ju D
通讯作者：
Ju D