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Published on: March 15, 2024
APR-246 induces early cell death by ferroptosis in acute myeloid leukemia
Rudy Birsen1, Clement Larrue2, Justine Decroocq3
1Université de Paris, Institut Cochin, CNRS UMR8104, INSERM U1016, Paris, France; Assistance Publique-Hôpitaux de Paris. Centre-Université de Paris, Service d'Hématologie clinique, Hôpital Cochin, Paris. rudy.birsen@inserm.fr.
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.
Insights
APR-246 induces cell death in acute myeloid leukemia (AML) by triggering ferroptosis, a process linked to lipid peroxidation. Enhancing ferroptosis synergistically increases cell death, offering a new therapeutic strategy for AML.
Area of Science:
- Biochemistry
- Oncology
- Cell Biology
Background:
- APR-246 is a novel therapeutic agent targeting p53 mutations in myelodysplastic syndromes and acute myeloid leukemia (AML).
- APR-246 reactivates p53 mutants and can induce p53-independent cell death in solid cancers.
Purpose of the Study:
- To investigate the mechanism of early cell death induced by APR-246 in AML.
- To determine if APR-246-induced cell death in AML fulfills the criteria for ferroptosis.
Main Methods:
- Treatment of AML cells with APR-246.
- Assessment of cell death using markers of lipid peroxidation.
- Inhibition of ferroptosis pathways using iron chelators, antioxidants, and lipid peroxidation inhibitors.
- Evaluation of synergistic effects with ferroptosis inducers (pharmacological and genetic).
Main Results:
- Early AML cell death following APR-246 exposure was suppressed by ferroptosis inhibitors and correlated with lipid peroxidation.
- AML cells increased cystine uptake to maintain glutathione biosynthesis, suggesting a role in detoxification.
- Combining APR-246 with ferroptosis inducers (e.g., SLC7A11 or GPX4 inactivation) resulted in synergistic cell death both in vitro and in vivo.
Conclusions:
- APR-246 induces ferroptosis in AML cells.
- The ability of AML cells to manage lipid peroxides influences sensitivity to APR-246.
- Targeting ferroptosis pathways alongside APR-246 presents a promising synergistic therapeutic strategy for AML.
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