文献类型：期刊文献

英文题名：Inhibition of mitochondrial complex III induces differentiation in acute myeloid leukemia

作者：Zhang, Youping[1];Luo, Ting[2];Ding, Xinyu[3];Chang, YungTing[4];Liu, Chuanxu[1];Zhang, Yongqiang[2];Hao, Siguo[1];Yin, Qianqian[3];Jiang, Biao[3,5]

机构：[1]Shanghai Jiao Tong Univ, Dept Hematol, Xin Hua Hosp, Sch Med, Shanghai 200092, Peoples R China;[2]East China Univ Sci & Technol, Sch Pharm, 130 Meilong Rd, Shanghai 200237, Peoples R China;[3]ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China;[4]Shanghai Jiao Tong Univ, Renji Hosp, Dept Pharm, Sch Med, Shanghai 200127, Peoples R China;[5]Chinese Acad Sci, Shanghai Inst Organ Chem, CAS Key Lab Synthet Chem Nat Subst, 345 Lingling Rd, Shanghai 200032, Peoples R China

年份：2021

卷号：547

起止页码：162

外文期刊名：BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000624915400008)】；

基金：This work was supported by grants from the National Natural Science Foundation of China (81702600, 81300404, 81873436 and 81873435).

语种：英文

外文关键词：Acute myeloid leukemia; Differentiation therapy; Mitochondrial ETC complex III; Pyrimidine biosynthesis

摘要：Although acute myeloid leukemia (AML) is a highly heterogeneous disease with diverse genetic subsets, one hallmark of AML blasts is myeloid differentiation blockade. Extensive evidence has indicated that differentiation induction therapy represents a promising treatment strategy. Here, we identified that the pharmacological inhibition of the mitochondrial electron transport chain (ETC) complex III by antimycin A inhibits proliferation and promotes cellular differentiation of AML cells. Mechanistically, we showed that the inhibition of dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme in de novo pyrimidine biosynthesis, is involved in antimycin A-induced differentiation. The activity of antimycin A could be reversed by supplement of excessive amounts of exogenous uridine as well as orotic acid, the product of DHODH. Furthermore, we also found that complex III inhibition exerts a synergistic effect in differentiation induction combined with DHODH inhibitor brequinar as well as with the pyrimidine salvage pathway inhibitor dipyridamole. Collectively, our study uncovered the link between mitochondrial complex III and AML differentiation and may provide further insight into the potential application of mitochondrial complex III inhibitor as a mono or combination treatment in differentiation therapy of AML. (c) 2021 Published by Elsevier Inc.