Abstract
CPX-351 is a liposomally encapsulated 5:1 molar ratio of cytarabine and daunorubicin that recently received regulatory approval for the treatment of therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes based on improved overall survival compared to standard cytarabine/daunorubicin therapy. Checkpoint kinase 1 (CHK1), which is activated by DNA damage and replication stress, diminishes sensitivity to cytarabine and anthracyclines as single agents, suggesting that CHK1 inhibitors might increase the effectiveness of CPX-351. The present studies show that CPX-351 activates CHK1 as well as the S and G2/M cell cycle checkpoints. Conversely, CHK1 inhibition diminishes the cell cycle effects of CPX-351. Moreover, CHK1 knockdown or addition of a CHK1 inhibitor such as MK-8776, rabusertib or prexasertib enhances CPX-351-induced apoptosis in multiple TP53-null and TP53-wildtype AML cell lines. Likewise, CHK1 inhibition increases the antiproliferative effect of CPX-351 on primary AML specimens ex vivo, offering the possibility that CPX-351 may be well suited to combine with CHK1-targeted agents.
Highlights
Despite advances in the molecular understanding of acute myeloid leukemia (AML), improvements in therapy are still needed
heat shock protein 90β (HSP90β) served as a loading control. (d) Dot plots of U937 cells treated for 24 h with diluent or CPX-351 in the presence of 5 μM Q-VD-OPh and, where indicated, 500 nM MK-8776
To assure that changes in propidium iodide staining were not a result of apoptosis-associated DNA fragmentation[19,20], the caspase inhibitor Q-VD-OPh21 was included in these assays
Summary
Despite advances in the molecular understanding of acute myeloid leukemia (AML), improvements in therapy are still needed. Alterations that prevent activation of the replication checkpoint such as inhibition or downregulation of CHK1 sensitize AML cells to cytarabine[7,8,9,10]. ® CPX-351 (Vyxeos ) is a liposomal formulation containing a synergistic 5:1 ratio of cytarabine and daunorubicin[13] This formulation has a number of appealing properties, including the ability to kill AML cells harboring certain resistance mechanisms[14] and a longer serum half-life than either cytarabine or daunorubicin[15]. (d) Dot plots of U937 cells treated for 24 h with diluent or CPX-351 (corresponding to cytarabine at 0.31 μM in the fixed combination with doxorubicin) in the presence of 5 μM Q-VD-OPh and, where indicated, 500 nM MK-8776. Results are mean ± sd of 4 independent experiments. *Indicates p < 0.01 compared to diluent or treatment with CPX-351 in the presence of MK-8776
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