APR-246 induces early cell death by ferroptosis in acute myeloid leukemia.

Abstract

APR-246 is a promising new therapeutic agent that targets p53 mutated proteins in myelodysplastic syndromes and in acute myeloid leukemia (AML). APR-246 reactivates the transcriptional activity of p53 mutants by facilitating their binding to DNA target sites. Recent studies in solid cancers have found that APR-246 can also induce p53-independent cell death. In this study, we demonstrate that AML cell death occurring early after APR-246 exposure is suppressed by iron chelators, lipophilic antioxidants and inhibitors of lipid peroxidation, and correlates with the accumulation of markers of lipid peroxidation, thus fulfilling the definition of ferroptosis, a recently described cell death process. The capacity of AML cells to detoxify lipid peroxides by increasing their cystine uptake to maintain major antioxidant molecule glutathione biosynthesis after exposure to APR-246 may be a key determinant of sensitivity to this compound. The association of APR-246 with induction of ferroptosis (either by pharmacological compounds, or genetic inactivation of SLC7A11 or GPX4) had a synergistic effect on the promotion of cell death, both in vivo and ex vivo.

• Authors: Rudy Birsen, Clement Larrue, Justine Decroocq, Natacha Johnson, Nathan Guiraud, Mathilde Gotanegre, Lilia Cantero-Aguilar, Eric Grignano, Tony Huynh, Michaela Fontenay, Olivier Kosmider, Patrick Mayeux, Nicolas Chapuis, Jean Emmanuel Sarry, Jerome Tamburini, Didier Bouscary
• Journal: Haematologica (Haematologica) Vol. 107 Issue 2 Pg. 403-416 (02 01 2022) ISSN: 1592-8721 [Electronic] Italy
• PMID: 33406814 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Quinuclidines
• eprenetapopt

Topics

• Cell Death
• Ferroptosis
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics, metabolism)
• Quinuclidines (therapeutic use)