Melatonin enhances sorafenib-induced cytotoxicity in FLT3-ITD acute myeloid leukemia cells by redox modification.,Theranostics

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Melatonin enhances sorafenib-induced cytotoxicity in FLT3-ITD acute myeloid leukemia cells by redox modification.
Theranostics ( IF 12.4 ) Pub Date : 2019-01-01 , DOI: 10.7150/thno.34327
Tian Tian ₁ , Jiajun Li ₁ , Yizhuo Li ₁ , Yun-Xin Lu ₁ , Yan-Lai Tang ₂ , Hua Wang ₁ , Fufu Zheng ₂ , Dingbo Shi ₁ , Qian Long ₁ , Miao Chen ₁ , Guillermo Garcia-Manero ₃ , Yumin Hu ₁ , Lijun Qin ₄ , Wuguo Deng ₁

Affiliation

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.

中文翻译：

褪黑素通过氧化还原修饰增强FLT3-ITD急性髓性白血病细胞中索拉非尼诱导的细胞毒性。

在Fms相关酪氨酸激酶3（FLT3-ITD）中具有内部串联重复的急性髓细胞白血病（AML）被确定为亚组，其结果较差且对化疗具有内在抗性，因此迫切需要开发新的治疗策略。方法：通过流式细胞术和免疫印迹法评估褪黑激素单独或与索拉非尼联合使用对FLT-ITD AML细胞的抗肿瘤作用。而且，离体和体内模型用于测试褪黑素和索拉非尼对具有FLT3 / ITD突变的白血病的协同作用。结果：我们的研究首次显示褪黑素抑制FLT3 / ITD阳性白血病细胞的增殖并诱导其凋亡。机械上，褪黑素优先导致活性氧（ROS）的过度产生，并最终导致FLT3-ITD AML细胞大量细胞死亡。此外，褪黑素通过氧化还原修饰显着增强了FLT3 / ITD对AML细胞中FLT3酪氨酸激酶抑制剂索拉非尼诱导的细胞毒性。重要的是，褪黑素和索拉非尼的组合在MV4-11异种移植物和带有FLT3 / ITD白血病的鼠模型中显示出高度协同的治疗活性。结论：这项研究表明，褪黑激素单独或与索拉非尼联合使用，有可能改善具有FLT3-ITD突变的AML患者的治疗结果，值得进一步研究。褪黑素通过氧化还原修饰显着增强FLT3酪氨酸激酶抑制剂索拉非尼在具有FLT3 / ITD的AML细胞中诱导的细胞毒性。重要的是，褪黑素和索拉非尼的组合在MV4-11异种移植物和带有FLT3 / ITD白血病的鼠模型中显示出高度协同的治疗活性。结论：这项研究表明，褪黑激素单独或与索拉非尼联合使用，有可能改善具有FLT3-ITD突变的AML患者的治疗结果，值得进一步研究。褪黑素通过氧化还原修饰显着增强FLT3酪氨酸激酶抑制剂索拉非尼在具有FLT3 / ITD的AML细胞中诱导的细胞毒性。重要的是，褪黑素和索拉非尼的组合在MV4-11异种移植物和带有FLT3 / ITD白血病的鼠模型中显示出高度协同的治疗活性。结论：这项研究表明，褪黑激素单独或与索拉非尼联合使用，有可能改善具有FLT3-ITD突变的AML患者的治疗结果，值得进一步研究。

更新日期：2019-01-01

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