Melatonin enhances sorafenib-induced cytotoxicity in FLT3-ITD acute myeloid leukemia cells by redox modification
Melatonin enhances sorafenib-induced cytotoxicity in FLT3-ITD acute myeloid leukemia cells by redox modification
复制标题
褪黑素通过氧化还原修饰增强索拉非尼诱导的FLT3-ITD急性髓系白血病细胞的细胞毒性
DOI：
10.7150/thno.34327
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Deng, Wuguo
中科院分区：
文献类型：
--
作者：
Tian, Tian;Li, Jiajun;Deng, Wuguo
急性髓细胞白血病（AML）伴FLT 3-ITD（Fms-related tyrosine kinase 3，FLT 3-ITD）基因内部串联重复突变（internal tandem duplication）是一种预后差、对化疗具有内在耐药性的亚群，因此迫切需要开发新的治疗策略。研究方法：在FLT-ITD AML细胞中，通过流式细胞术和免疫印迹分析评估褪黑激素单独或与索拉非尼组合的抗肿瘤作用。此外，使用离体和体内模型来测试褪黑激素和索拉非尼对具有FLT 3/ITD突变的白血病的协同作用。结果：我们的研究首次表明，褪黑激素抑制FLT 3/ITD阳性白血病细胞的增殖和诱导凋亡。从机制上讲，褪黑激素优先导致活性氧（ROS）的过度产生，并最终导致FLT 3-ITD AML细胞的大量细胞死亡。此外，褪黑激素通过氧化还原修饰显著增强FLT 3酪氨酸激酶抑制剂索拉非尼在具有FLT 3/ITD的AML细胞中诱导的细胞毒性。重要的是，褪黑激素和索拉非尼的组合在MV 4 -11异种移植物和携带FLT 3/ITD白血病的鼠模型中表现出高度协同的治疗活性。结论：这项研究表明，褪黑激素单独使用或与索拉非尼联合使用有可能改善具有FLT 3-ITD突变的AML患者的治疗结果，值得进一步研究。
Acute myeloid leukemia (AML) with an internal tandem duplication in Fms-related tyrosine kinase 3 (FLT3-ITD) is identified as a subgroup with poor outcome and intrinsic resistance to chemotherapy and therefore urgent need for development of novel therapeutic strategies. Methods: The antitumor effects of melatonin alone or combined with sorafenib were evaluated via flow cytometry and immunoblotting assays in FLT-ITD AML cells. Also, the ex vivo and in vivo models were used to test the synergistic effects of melatonin and sorafenib against leukemia with FLT3/ITD mutation. Results: Our study shows for the first time that melatonin inhibits proliferation and induces apoptosis in FLT3/ITD-positive leukemia cells. Mechanistically, melatonin preferentially causes overproduction of reactive oxygen species (ROS) and ultimately massive cell death in FLT3-ITD AML cells. Moreover, melatonin significantly enhances the cytotoxicity induced by the FLT3 tyrosine kinase inhibitor sorafenib in AML cells with FLT3/ITD through redox modification. Importantly, combination of melatonin and sorafenib exhibited highly synergistic therapeutic activity in MV4-11 xenografts and a murine model bearing FLT3/ITD leukemia. Conclusion: This study indicates that melatonin, alone or in combination with sorafenib, has potential to improve the therapeutic outcome of AML patients with FLT3-ITD mutation that merits further investigation.