HDAC I/IIb selective inhibitor Purinostat Mesylate combined with GLS1 inhibition effectively eliminates CML stem cells  

作　　者：Qiang Qiu Linyu yang Yunyu Feng Zejiang Zhu Ning Li Li Zheng Yuanyuan Sun Cong Pan Huandi Qiu Xue Cui Wei He Fang Wang Yuyao Yi Minghai Tang Zhuang Yang Yunfan Yang Zhihui Li Lijuan Chen Yiguo Hu 

机构地区：[1]State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,Sichuan University,and Collaborative Innovation Center for Biotherapy,Chengdu,PR China [2]Thyroid and Parathyroid Surgery Center,State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,Sichuan University,Chengdu,PR China [3]Department of Hematology and Research Laboratory of Hematology,West China Hospital,Sichuan University,Chengdu,PR China [4]Center of Infectious Diseases,West China Hospital,Sichuan University,Chengdu,PR China [5]Guizhou Normal College,Guiyang,PR China

出　　处：《Bioactive Materials》2023年第3期483-498,共16页生物活性材料（英文）

基　　金：Fundamental Research Funds for the Central Universities(2021SCU12022 to L.Yang);the 1.3.5 Project for Disciplines of Excellence(to Z.Li and L.Chen);West China Hospital,Sichuan University,the National Natural Science Foundation of China(82104211 to L.Yang);National Natural Science Foundation of China(81541092 and 81770103 to Y.Hu).

摘　　要：Purinostat Mesylate(PM)is a novel highly selective and active HDAC I/IIb inhibitor,and the injectable formulation of PM(PMF)based on the compound prescription containing cyclodextrin completely can overcome PM’s poor solubility and improves its stability and pharmacokinetic properties.Here,we showed that PM effectively repressed the survival of Ph+leukemia cells and CD34+leukemia cells from CML patients in vitro.In vivo studies demonstrated that PMF significantly prevented BCR-ABL(T315I)induced CML progression by restraining leukemia stem cells(LSCs),which are insensitive to chemotherapy and responsible for CML relapse.Mechanism studies revealed that targeting HDAC I/IIb repressed several important factors for LSCs survival including c-Myc,β-Catenin,E2f,Ezh2,Alox5,and mTOR,as well as interrupted some critical biologic processes.Additionally,PMF increased glutamate metabolism in LSCs by increasing GLS1.The combination of PMF and glutaminase inhibitor BPTES synergistically eradicated LSCs by altering multiple key proteins and signaling pathways which are critical for LSC survival and self-renewal.Overall,our findings represent a new therapeutic strategy for eliminating LSCs by targeting HDAC I/IIb and glutaminolysis,which potentially provides a guidance for PMF clinical trials in the future for TKI resistance CML patients.

关 键 词：Chronic myelogenous leukemia Leukemia stem cell Selective HDAC I/IIb inhibitor GLS1 Mouse model 

分 类 号：R733.7[医药卫生—肿瘤]