title: Guaianolide sesquiterpene lactones, a source to discover agents that selectively inhibit acute myelogenous leukemia stem and progenitor cells.
abstract: Small molecules that can selectively target cancer stem cells (CSCs) remain rare currently and exhibit no common structural features. Here we report a series of guaianolide sesquiterpene lactones (GSLs) and their derivatives that can selectively eradicate acute myelogenous leukemia (AML) stem or progenitor cells. Natural GSL compounds arglabin, an anticancer clinical drug, and micheliolide (MCL), are able to reduce the proportion of AML stem cells (CD34⁺CD38⁻) in primary AML cells. Targeting of AML stem cells is further confirmed by a sharp reduction of colony-forming units of primary AML cells upon MCL treatment. Moreover, DMAMCL, the dimethylamino Michael adduct of MCL, slowly releases MCL in plasma and in vivo and demonstrates remarkable therapeutic efficacy in the nonobese diabetic/severe combined immunodeficiency AML models. These findings indicate that GSL is an ample source for chemical agents against AML stem or progenitor cells and that GSL is potentially highly useful to explore anti-CSC approaches.
authors.affiliation: College of Pharmacy and The State Key Laboratory of Elemento-Organic Chemistry, Nankai University, and State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences, Tianjin, People's Republic of China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhang
authors.forename: Yaxin
authors.initials: Y
authors.lastname: Lu
authors.forename: Yahui
authors.initials: Y
authors.lastname: Ding
authors.forename: Jiadai
authors.initials: J
authors.lastname: Zhai
authors.forename: Qing
authors.initials: Q
authors.lastname: Ji
authors.forename: Weiwei
authors.initials: W
authors.lastname: Ma
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.forename: Hongxia
authors.initials: H
authors.lastname: Fan
authors.forename: Jing
authors.initials: J
authors.lastname: Long
authors.forename: Zhongsheng
authors.initials: Z
authors.lastname: Tong
authors.forename: Yehui
authors.initials: Y
authors.lastname: Shi
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Jia
authors.forename: Bin
authors.initials: B
authors.lastname: Han
authors.forename: Wenpeng
authors.initials: W
authors.lastname: Zhang
authors.forename: Chuanjiang
authors.initials: C
authors.lastname: Qiu
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Ma
authors.forename: Qiuying
authors.initials: Q
authors.lastname: Li
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Shi
authors.forename: Haoliang
authors.initials: H
authors.lastname: Zhang
authors.forename: Dongmei
authors.initials: D
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Jianping
authors.initials: J
authors.lastname: Lin
authors.forename: Lu-Yuan
authors.initials: LY
authors.lastname: Li
authors.forename: Yingdai
authors.initials: Y
authors.lastname: Gao
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology; D045789:Sesquiterpenes, Guaiane / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D007783:Lactones; D011355:Prodrugs; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; C577929:dimethylaminomicheliolide; C577928:micheliolide; C083346:arglabin