Dysregulation of MDM2, a p53 negative regulator, frequently occurs in
acute myeloid leukemia (AML) and is associated with unfavorable prognoses, rendering the p53-MDM2 axis an attractive target for the development of small-molecule inhibitors. MDM2 antagonists have been intensely developed but only lead to limited clinical activity, suggesting combination with additional drugs is an unmet medical need. In this study, we reported that
Triptolide synergized with MDM2 inhibitor
Nutlin-3a to suppress cell proliferation and induce mitochondrial-mediated apoptosis in p53 wt AML in vitro and ex vivo. More importantly,
Triptolide cooperated with
Nutlin-3a to delay
tumor growth and abrogate
leukemia burden in an AML xenograft model. In addition, we observed that
Triptolide and
Nutlin-3a were also cooperative in part of p53 deficient cases. Mechanistically,
Nutlin-3a upregulated the transcriptional expressions of the p53 downstream targets PUMA and p21, while
Triptolide declined the
mRNA levels of two anti-apoptotic factors, XIAP and Mcl-1, in p53 wt cells. These effects were more notable when
Triptolide and
Nutlin-3a were combined. Our results revealed that
Triptolide monotherapy exerted its antileukemia effect via both p53-dependent and independent ways, with the latter through perturbation of the MYC-ATF4 axis-mediated ER stress. Collectively, these data suggested that the Triptolide-Nutlin-3a combination might be a novel potential therapeutic intervention for patients with AML and it warrants further clinical evaluations.