Therapeutic synergy of Triptolide and MDM2 inhibitor against acute myeloid leukemia through modulation of p53-dependent and -independent pathways

Abstract

Abstract 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.

Keywords

• Acute myeloid leukemia (AML)
• p53
• MDM2 inhibitor
• Triptolide
• MYC
• ATF4