Dispirocyclopropyldehydrocostus lactone selectively inhibits acute myelogenous leukemia cells

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• 作者：Ya-Hui Ding^a ; ^&dagger ; ; Xue Gao^b ; ^&dagger ; ; Jing Long^a ; Bei-Jia Kuang^a ; Yue Chen^a ; ^{yuechen@nankai.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Quan Zhang^a ; ^{zhangquan612@163.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Acute myeloid leukemia ; Sesquiterpene lactone ; Apoptosis
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 February 2016
• 年：2016
• 卷：26
• 期：4
• 页码：1165-1168
• 全文大小：870 K

文摘

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.