title: Dispirocyclopropyldehydrocostus lactone selectively inhibits acute myelogenous leukemia cells.
abstract: Acute myeloid leukemia (AML) is a refractory disease, and the majority of AML patients died from relapse and multidrug resistance. More and more studies demonstrate that AML stem cells play key role in multidrug resistance of AML. Here, we report a derivative of dehydrocostus lactone, that is, dispirocyclopropyldehydrocostus lactone (DDL), showed preferable cytotoxicity against a series of leukemia cell lines and AML stem cells from clinical samples of AML patient. Meanwhile, DDL demonstrated no significant toxicity to normal hematopoietic cells. Therefore, the prodrug of DDL, DMADDL, was evaluated for its in vivo anti-AML activity. The result revealed that DMADDL could inhibit the tumor growth in SCID mice tumorigenicity assay. Further study suggested that DDL induced apoptosis mainly through the up-regulation of apoptosis related protein Bax, followed by the cleavage of caspase-3, caspase-9, and PARP.
authors.affiliation: College of Pharmacy, The State Key Laboratory of Elemento-Organic Chemistry, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China.
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Ding
authors.affiliation: College of Pharmacy, Binzhou Medical University, Yantai 264000, PR China.
authors.forename: Xue
authors.initials: X
authors.lastname: Gao
authors.affiliation: College of Pharmacy, The State Key Laboratory of Elemento-Organic Chemistry, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Long
authors.affiliation: College of Pharmacy, The State Key Laboratory of Elemento-Organic Chemistry, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China.
authors.forename: Bei-Jia
authors.initials: BJ
authors.lastname: Kuang
authors.affiliation: College of Pharmacy, The State Key Laboratory of Elemento-Organic Chemistry, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China. Electronic address: yuechen@nankai.edu.cn.
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.affiliation: College of Pharmacy, The State Key Laboratory of Elemento-Organic Chemistry, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China. Electronic address: zhangquan612@163.com.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D012717:Sesquiterpenes / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D007783:Lactones; D011355:Prodrugs; D012717:Sesquiterpenes; D051028:bcl-2-Associated X Protein; C083030:dehydrocostus lactone; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D053453:Caspase 9
keywords: Acute myeloid leukemia; Apoptosis; Sesquiterpene lactone