期刊
HAEMATOLOGICA
卷 107, 期 2, 页码 403-416出版社
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2020.259531
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类别
资金
- Association de Recherche Contre le Cancer (ARC) [DOC20170505807, DOC20190508975, M2R20180507379]
- Institut National du Cancer [ASC16046KSA]
- Ligue Nationale Contre le Cancer (LNCC) [ELFUZ17337, IP/SCG/JD-16129]
- association Laurette Fugain [ALF2018/02]
APR 246 is a promising therapeutic agent for myelodysplastic syndromes and acute myeloid leukemia that targets p53 mutated proteins. It has been found to reactivate the transcriptional activity of p53 mutants and induce p53-independent cell death. The study also demonstrates the association between APR 246 and ferroptosis, a recently described cell death process. The detoxification capacity of AML cells to maintain glutathione biosynthesis may play a key role in determining sensitivity to APR 246.
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.
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