多巴酚丁胺可增强奎扎替尼对FLT3-ITD突变型急性髓系白血病的靶向抑制作用  

Dobutamine Enhances the Targeted Inhibitory Effect of Quizartinib on FLT3-ITD Mutant Acute Myeloid Leukemia

作　　者：高宇昂 张倩钰 李欣 王绅宇 李芨慧 薛阳 李长燕 宁红梅 GAO Yu-Ang;ZHANG Qian-Yui;LI Xin;WANG Shen-Yu;LI Ji-Hui;XUE Yang;UI Chang-Yan;NING Hong-Mei(Gradute School of the Chinese PLA Medical School,Beijing 100071,China;Department of Hematology,The Fifth Medical Center,General Hospital of the People's Liberation Amny,Beijig 100071,China;The Fifth Medical Clinical College of the General Hospital of the PLA,Anhui Medical University,Hefei 230032,Anhui Province,China;Department of Ultrasound,Eighth Medical Center,General Hospital of the People's Liberation Amny,Beijing 100091,China;Institute of Radiation Medicine,Instirute of Military Medical Research,Chinese People's Liberution Army Academy of Miliary Sciences,Beijing 100850,China)

机构地区：[1]解放军医学院研究生院 [2]中国人民解放军总医院第五医学中心血液病医学部,北京100071 [3]安徽医科大学解放军总医院第五医学临床学院,合肥230032 [4]中国人民解放军总医院第八医学中心超声科,北京100091 [5]中国人民解放军军事科学院军事医学研究院辐射医学研究所,北京100850

出　　处：《中国实验血液学杂志》2024年第4期1071-1077,共7页Journal of Experimental Hematology

摘　　要：目的:观察多巴酚丁胺对人FLT3-ITD突变型急性髓系白血病(AML)细胞的增殖抑制作用,探讨多巴酚丁胺单药或者联合奎扎替尼治疗该型AML的可行性。方法:体外培养FLT3-ITD突变AML细胞系MOLM13及MV4-11,实验分为对照组、多巴酚丁胺处理组、奎扎替尼处理组、多巴酚丁胺联合奎扎替尼处理组,采用CCK-8法、流式细胞术分别检测各组细胞活性、细胞凋亡率及ROS水平,并通过Western blot检测YAP1蛋白的表达。结果:多巴酚丁胺和奎扎替尼均可抑制FLT3-ITD突变型AML细胞系MOLM13、MV4-11的增殖。与对照组相比,多巴酚丁胺组FLT3-ITD突变AML细胞的ROS水平显著上升(P<0.01),凋亡率增加(P<0.05),其YAP1蛋白的表达减少(P<0.05);与多巴酚丁胺组相比,奎扎替尼联合多巴酚丁胺组的细胞活性显著降低(P<0.05),ROS水平上升(P<0.01),YAP1表达减少(P<0.05)。结论:多巴酚丁胺单药可抑制FLT3-ITD突变型AML细胞的增殖,引起其凋亡,且联合奎扎替尼可增强对FLT3-ITD突变型急性髓性白血病的靶向抑制作用。其机制可能是通过抑制该型AML细胞YAP1蛋白的表达,提高ROS水平从而发挥其抗肿瘤作用。Objective:To observe the inhibitory effect of dobutamine on proliferation of FLT3-ITD mutated acute myeloid leukemia(AML)cells and explore the feasibility of dobutamine as a monotherapy or in combination with quizartinib for the treatment of this type of AML.Methods:FLT3-ITD mutant cell lines MOLM13and MV4-11 were cultured in vitro and divided into control group,dobutamine treatment group,quizartinib treatment group,and dobutamine combined with quizartinib treatment group.Cell viability,ROS levels,and apoptosis rate were detected by CCK-8,Flow cytometry,respectively,as well as the expression of YAP1protein by Western blot.Results:Both dobutamine and quizartinib inhibited the proliferation of FLT3-ITD mutant AML cell lines.Compared with the control group,the dobutamine group exhibited a significant increase in ROS levels(P<0.01),an increase in apoptosis rates(P<0.05),and a decrease in YAP1protein expression(P<0.05).Compared with the dobutamine group,the combination of quizartinib and dobutamine significantly reduced cell viability(P<0.05),increased ROS levels(P<0.01),and decreased YAP1expression(P<0.05).Conclusion:Dobutamine as a monotherapy can inhibit the proliferation of FLT3-ITD mutated AML cells,inducing apoptosis.Additionally,the combination of quizartinib enhances the targeted inhibitory effect on FLT3-ITD mutated AML.The mechanism may involve the inhibition of YAP1protein expression in AML cells of this type,leading to an increase in ROS levels and exerting its anti-tumor effects.

关 键 词：急性髓系白血病 fms样酪氨酸激酶3 多巴酚丁胺 YAP1 

分 类 号：R733.7[医药卫生—肿瘤]