title: Antineoplastic effects and mechanisms of micheliolide in acute myelogenous leukemia stem cells.
abstract: Leukemic stem cells (LSCs) greatly contribute to the initiation, relapse, and multidrug resistance of leukemia. Current therapies targeting the cell cycle and rapidly growing leukemic cells, including conventional chemotherapy, have little effect due to the self-renewal and differentiated malignant cells replenishment ability of LSCs despite their scarce supply in the bone marrow. Micheliolide (MCL) is a natural guaianolide sesquiterpene lactone (GSL) which was discovered in michelia compressa and michelia champaca plants, and has been shown to exert selective cytotoxic effects on CD34+CD38- LSCs. In this study, we demonstrate that DMAMCL significantly prolongs the lifespan of a mouse model of human acute myelogenous leukemia (AML). Mechanistic investigations further revealed that MCL exerted its cytotoxic effects via inhibition of NF-κB expression and activity, and by generating intracellular reactive oxygen species (ROS). These results provide valuable insight into the mechanisms underlying MCL-induced cytotoxicity of LSCs, and support further preclinical investigations of MCL-related therapies for the treatment of AML.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China.|The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China.
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China.
authors.forename: Hui-Er
authors.initials: HE
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China.
authors.forename: He-Nan
authors.initials: HN
authors.lastname: Song
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China.
authors.forename: Xiao-Lei
authors.initials: XL
authors.lastname: Liu
authors.affiliation: Department of Stomatology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China.
authors.forename: Zi-Xiang
authors.initials: ZX
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China.
authors.forename: Ying-Hui
authors.initials: YH
authors.lastname: Li
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P. R. China.
authors.forename: Ying-Dai
authors.initials: YD
authors.lastname: Gao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D000066673:Cell Self Renewal / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D029562:Magnoliaceae / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D045789:Sesquiterpenes, Guaiane / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D045789:Sesquiterpenes, Guaiane; C577928:micheliolide
keywords: leukemic stem cells; micheliolide