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hdac i/iib selective inhibitor Purinostat Mesylate combined with GLS1 inhibition effectively eliminates CML stem cells

引用

Bioactive Materials 2023年第3期21卷 483-498页

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 State Key Laboratory of Biotherapy and Cancer Center West China HospitalSichuan Universityand Collaborative Innovation Center for BiotherapyChengduPR China Thyroid and Parathyroid Surgery Center State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduPR China Department of Hematology and Research Laboratory of Hematology West China HospitalSichuan UniversityChengduPR China Center of infectious Diseases West China HospitalSichuan UniversityChengduPR China Guizhou Normal College GuiyangPR China

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 ***,we showed that PM effectively repressed the survival of Ph+leukemia cells and CD34+leukemia cells from CML patients 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 *** 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 ***,PMF increased glutamate metabolism in LSCs by increasing *** 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 ***,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

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