Dispirocyclopropyldehydrocostus lactone selectively inhibits acute myelogenous leukemia cells

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.

Graphical abstractAcute 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.Figure optionsDownload full-size imageDownload as PowerPoint slide