Antileukemic efficacy of a potent artemisinin combined with sorafenib and venetoclax.
AuthorMoses, Blake S
Fox, Jennifer M
Mott, Bryan T
Bentzen, Søren M
Tyner, Jeffrey W
Lapidus, Rena G
Rudek, Michelle A
Kingsbury, Tami J
Civin, Curt I
PublisherAmerican Society of Hematology
MetadataShow full item record
AbstractArtemisinins 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.
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/14928
- A Novel MCL1 Inhibitor Combined with Venetoclax Rescues Venetoclax-Resistant Acute Myelogenous Leukemia.
- Authors: Ramsey HE, Fischer MA, Lee T, Gorska AE, Arrate MP, Fuller L, Boyd KL, Strickland SA, Sensintaffar J, Hogdal LJ, Ayers GD, Olejniczak ET, Fesik SW, Savona MR
- Issue date: 2018 Dec
- A Novel 2-Carbon-Linked Dimeric Artemisinin With Potent Antileukemic Activity and Favorable Pharmacology.
- Authors: Kagan AB, Moses BS, Mott BT, Rai G, Anders NM, Rudek MA, Civin CI
- Issue date: 2021
- Artemisinin-derived dimer ART-838 potently inhibited human acute leukemias, persisted in vivo, and synergized with antileukemic drugs.
- Authors: Fox JM, Moynihan JR, Mott BT, Mazzone JR, Anders NM, Brown PA, Rudek MA, Liu JO, Arav-Boger R, Posner GH, Civin CI, Chen X
- Issue date: 2016 Feb 9
- Concomitant targeting of BCL2 with venetoclax and MAPK signaling with cobimetinib in acute myeloid leukemia models.
- Authors: Han L, Zhang Q, Dail M, Shi C, Cavazos A, Ruvolo VR, Zhao Y, Kim E, Rahmani M, Mak DH, Jin SS, Chen J, Phillips DC, Koller PB, Jacamo R, Burks JK, DiNardo C, Daver N, Jabbour E, Wang J, Kantarjian HM, Andreeff M, Grant S, Leverson JD, Sampath D, Konopleva M
- Issue date: 2020 Mar
- Inhibition of Bcl-2 Synergistically Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Preclinical Models of FLT3-Mutated Acute Myeloid Leukemia.
- Authors: Ma J, Zhao S, Qiao X, Knight T, Edwards H, Polin L, Kushner J, Dzinic SH, White K, Wang G, Zhao L, Lin H, Wang Y, Taub JW, Ge Y
- Issue date: 2019 Nov 15