阿扎胞苷联合高三尖杉酯碱通过调控c-MYC/DDIT3/PUMA轴协同抗急性髓系白血病的研究  

Synergistic effect of azacitidine with homoharringtonine by activating the c-MYC/DDIT3/PUMA axis in acute myeloid leukemia

作　　者：李军 黄炎青[1] 訾杰 Song Chunhua 葛峥[1] Li Jun;Huang Yanqing;Zi Jie;Chunhua Song;Ge Zheng(Department of Hematology,Zhongda Hospital,School of Medicine,Southeast University,Institute of Hematology Southeast University,Nanjing 210009,China;Pennysvinia State University,College of Medicine and Hershey Medical Center,Hershey,PA 17033,USA;Division of Hematology,The Ohio State University Wexner Medical Center and The James Cancer Hospital,Columbus,OH 43210,USA)

机构地区：[1]东南大学附属中大医院血液科,东南大学血液病研究所,南京210009 [2]Pennysvinia State University,College of Medicine and Hershey Medical Center,Hershey,PA 17033,USA [3]The Ohio State University,Wexner Medical Center and The James Cancer Hospital,Columbus,OH 43210,USA

出　　处：《中华血液学杂志》2023年第12期1001-1009,共9页Chinese Journal of Hematology

基　　金：江苏省卫健委医学科研重点项目(ZD2021003);江苏省医学重点学科建设单位(JSDW202212);江苏省研究生科研与实践创新计划项目(KYCX22_0296)。

摘　　要：目的探索阿扎胞苷(AZA)联合高三尖杉酯碱(HHT)治疗急性髓系白血病(AML)的协同效应及其分子机制。方法采用细胞增殖、凋亡和克隆形成实验研究AZA联合HHT在AML中协同效应并计算两药协同效应指数(CI),通过转录组测序、通路抑制剂和基因敲降等方法,探索两药的协同机制。结果与单药相比,AZA+ HHT可显著抑制AML细胞增殖,并具有显著的协同效应(U937、MV4-11和KG-1细胞中CI值均小于0.9);AZA+HHT能显著抑制U937(P<0.001)和MV4-11(P<0.001)细胞的克隆形成,并显著促进U937(P<0.001)和MV4-11(P<0.001)细胞凋亡。AZA联合HHT通过激活整合应激反应(ISR)信号通路介导DDIT3-PUMA依赖的AML细胞凋亡。AZA联合HHT可明显下调c-MYC蛋白,通过激活ISR信号通路,调控c-MYC/DDIT3/PUMA轴,促进细胞凋亡发挥协同抗AML作用。结论 AZA联合HHT通过激活ISR信号通路,调控c-MYC/DDIT3/PUMA轴,抑制细胞增殖和促进细胞凋亡,发挥协同抗AML作用。Objective This study aimed to explore the synergistic effect and underlying mechanism of azacitidine(AZA)in combination with homoharringtonine(HHT)in acute myeloid leukemia(AML).Methods The synergistic effects of AZA and HHT were examined by cell proliferation,apoptosis,and colony formation assays.The synergistic effects were calculated using the combination index(CI),and the underlying mechanisms were explored using RNA sequencing,pathway inhibitors,and gene knockdown approaches.Results Compared with the single-drug controls,AZA and HHT combination significantly induced cell proliferation arrest and showed a synergistic effect with CI<0.9 in AML cells.In the combination group versus the single-drug controls,colony formation was significantly decreased,whereas apoptosis was significantly increased in U937(P<0.001)and MV4-11(P<0.001)cells.AZA and HHT combination activated the integrated stress response(ISR)signaling pathway and induced DDIT3-PUMA-dependent apoptosis in cells.Furthermore,it remarkably downregulated the expression of c-MYC.The combination also activated c-MYC/DDIT3/PUMA-mediated ISR signaling to induce synergy on apoptosis.The synergy of AZA+HHT on apoptosis was induced by activating c-MYC/DDIT3/PUMA-mediated ISR signaling.Conclusion The combination of AZA and HHT exerts synergistic anti-AML effects by inhibiting cellular proliferation and promoting apoptosis through activation of the ISR signaling pathway via the c-MYC/DDIT3/PUMA axis.

关 键 词：阿扎胞苷 高三尖杉酯碱 白血病 髓系 急性 协同效应 

分 类 号：R733.71[医药卫生—肿瘤]