Antileukemic efficacy of a potent artemisinin combined with sorafenib and venetoclax.
Author
Moses, Blake SMcCullough, Samantha
Fox, Jennifer M
Mott, Bryan T
Bentzen, Søren M
Kim, MinJung
Tyner, Jeffrey W
Lapidus, Rena G
Emadi, Ashkan
Rudek, Michelle A
Kingsbury, Tami J
Civin, Curt I
Date
2021-02-02Journal
Blood AdvancesPublisher
American Society of HematologyType
Article
Metadata
Show full item recordAbstract
Artemisinins are active against human leukemia cell lines and have low clinical toxicity in worldwide use as antimalarials. Because multiagent combination regimens are necessary to cure fully evolved leukemias, we sought to leverage our previous finding that artemisinin analogs synergize with kinase inhibitors, including sorafenib (SOR), by identifying additional synergistic antileukemic drugs with low toxicity. Screening of a targeted antineoplastic drug library revealed that B-cell lymphoma 2 (BCL2) inhibitors synergize with artemisinins, and validation assays confirmed that the selective BCL2 inhibitor, venetoclax (VEN), synergized with artemisinin analogs to inhibit growth and induce apoptotic cell death of multiple acute leukemia cell lines in vitro. An oral 3-drug “SAV” regimen (SOR plus the potent artemisinin-derived trioxane diphenylphosphate 838 dimeric analog [ART838] plus VEN) killed leukemia cell lines and primary cells in vitro. Leukemia cells cultured in ART838 had decreased induced myeloid leukemia cell differentiation protein (MCL1) levels and increased levels of DNA damage-inducible transcript 3 (DDIT3; GADD153) messenger RNA and its encoded CCATT/enhancer-binding protein homologous protein (CHOP), a key component of the integrated stress response. Thus, synergy of the SAV combination may involve combined targeting of MCL1 and BCL2 via discrete, tolerable mechanisms, and cellular levels of MCL1 and DDIT3/CHOP may serve as biomarkers for action of artemisinins and SAV. Finally, SAV treatment was tolerable and resulted in deep responses with extended survival in 2 acute myeloid leukemia (AML) cell line xenograft models, both harboring a mixed lineage leukemia gene rearrangement and an FMS-like receptor tyrosine kinase-3 internal tandem duplication, and inhibited growth in 2 AML primagraft models.Rights/Terms
© 2021 by The American Society of Hematology.Keyword
artemisininebcl2 gene
bcl-2 protein
cell lines
cyclophosphamide
doxorubicin
prednisone
vincristine
leukemia
leukemia, acute
sorafenib
transplantation
heterologous
venetoclax
Identifier to cite or link to this item
http://hdl.handle.net/10713/14928ae974a485f413a2113503eed53cd6c53
10.1182/bloodadvances.2020003429
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