APR-246 induces early cell death by ferroptosis in acute myeloid leukemia.
APR-246 induces early cell death by ferroptosis in acute myeloid leukemia.
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DOI：
10.3324/haematol.2020.259531
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发表时间：
2022-02-01
期刊：
影响因子：
10.1
通讯作者：
Bouscary D
中科院分区：
文献类型：
--
作者：
Birsen R;Larrue C;Decroocq J;Johnson N;Guiraud N;Gotanegre M;Cantero-Aguilar L;Grignano E;Huynh T;Fontenay M;Kosmider O;Mayeux P;Chapuis N;Sarry JE;Tamburini J;Bouscary D
APR-246是一种有前途的新治疗药物，靶向骨髓增生异常综合征和急性髓性白血病（AML）中的p53突变蛋白。APR-246通过促进p53突变体与DNA靶位点的结合来重新激活p53突变体的转录活性。最近在实体癌中的研究发现，APR-246也可以诱导p53非依赖性细胞死亡。在这项研究中，我们证明了APR-246暴露后早期发生的AML细胞死亡受到铁螯合剂，亲脂性抗氧化剂和脂质过氧化抑制剂的抑制，并与脂质过氧化标志物的积累相关，从而符合铁凋亡的定义，这是一种最近描述的细胞死亡过程。AML细胞在暴露于APR-246后通过增加其胱氨酸摄取来解毒脂质过氧化物以维持主要抗氧化分子谷胱甘肽生物合成的能力可能是对该化合物敏感性的关键决定因素。APR-246与诱导铁凋亡（通过药理学化合物或SLC 7A 11或GPX 4的遗传失活）的关联在体内和离体都对促进细胞死亡具有协同作用。
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.
影响因子：
6.4
作者：
Duan, Wenrui;Gao, Li;Wu, Xin;Wang, Li;Nana-Sinkam, Serge P.;Otterson, Gregory A.;Villalona-Calero, Miguel A.
通讯作者：
Villalona-Calero, Miguel A.