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...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.展开更多
缺血性脑卒中是一种由于脑部供血受阻导致缺血灶不可逆损伤的中枢神经系统疾病,其发病突然、传变迅速、病程复杂,静脉溶栓和血管内介入是早期干预的主要措施,但时间窗和禁忌症使其应用受到限制。丹参Salviae Miltiorrhizae Radix et Rhi...缺血性脑卒中是一种由于脑部供血受阻导致缺血灶不可逆损伤的中枢神经系统疾病,其发病突然、传变迅速、病程复杂,静脉溶栓和血管内介入是早期干预的主要措施,但时间窗和禁忌症使其应用受到限制。丹参Salviae Miltiorrhizae Radix et Rhizoma为传统中药材,其中丹参酮类脂溶性成分治疗缺血性脑卒中疗效确切并在临床广泛应用。总结了丹参酮类脂溶性成分干预缺血性脑卒中的可能机制,包括抗凋亡、抗炎、调节自噬、限制谷氨酸兴奋性毒性、抑制氧化应激、促进新生血管形成等,以期为临床应用提供一定的借鉴。展开更多
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)+1 种基金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).
文摘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.
文摘缺血性脑卒中是一种由于脑部供血受阻导致缺血灶不可逆损伤的中枢神经系统疾病,其发病突然、传变迅速、病程复杂,静脉溶栓和血管内介入是早期干预的主要措施,但时间窗和禁忌症使其应用受到限制。丹参Salviae Miltiorrhizae Radix et Rhizoma为传统中药材,其中丹参酮类脂溶性成分治疗缺血性脑卒中疗效确切并在临床广泛应用。总结了丹参酮类脂溶性成分干预缺血性脑卒中的可能机制,包括抗凋亡、抗炎、调节自噬、限制谷氨酸兴奋性毒性、抑制氧化应激、促进新生血管形成等,以期为临床应用提供一定的借鉴。
