Inhibition of the redox function of APE1/Ref-1 in myeloid leukemia cell lines results in a hypersensitive response to retinoic acid-induced differentiation and apoptosis.
Inhibition of the redox function of APE1/Ref-1 in myeloid leukemia cell lines results in a hypersensitive response to retinoic acid-induced differentiation and apoptosis.
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DOI：
10.1016/j.exphem.2010.08.011
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发表时间：
2010-12
影响因子：
2.6
通讯作者：
Robertson, Kent A.
中科院分区：
文献类型：
--
作者：
Fishel, Melissa L.;Colvin, E. Scott;Luo, Meihua;Kelley, Mark R.;Robertson, Kent A.
早幼粒细胞白血病的标准治疗包括使用分化剂全反式维甲酸（RA）和化疗。RA通过视黄酸受体（RAR）转录因子诱导细胞分化。由于氧化还原机制影响转录因子与DNA反应元件（RARE）结合的容易程度，因此研究了小分子（E3330）抑制氧化还原调节蛋白、脱嘌呤-脱嘧啶核酸内切酶/氧化还原效应因子（APE 1/Ref-1）对RA诱导的髓性白血病细胞分化和凋亡中RAR DNA结合和功能的影响。用小分子抑制剂E3330研究了APE 1在HL-60和PLB急性髓系白血病细胞中的氧化还原功能。采用电泳迁移率变动分析（EMSA）检测抑制剂对APE 1/Ref-1氧化还原信号功能的影响。采用台盼蓝染色、Annexin-V/PI和CD 11 b染色以及真实的实时PCR分析来确定培养中细胞的存活、凋亡和分化状态。RARα通过APE 1/Ref-1氧化还原调节以氧化还原依赖性方式与其RARE结合。氧化还原依赖性RAR-RARE结合被APE 1/Ref-1的小分子氧化还原抑制剂E3330阻断。RA + E3330联合治疗导致髓系白血病细胞对RA诱导的分化和凋亡的高度超敏反应。此外，E3330的氧化还原抑制导致骨髓白血病细胞中RAR靶基因BLR-1的表达增强。APE 1/Ref-1的氧化还原功能调节RAR与其DNA RARE的结合，影响髓性白血病细胞对RA诱导分化的反应。靶向APE 1/Ref-1氧化还原功能可能允许操纵具有治疗意义的类维生素A反应。
The standard of care for promyelocytic leukemia includes use of the differentiating agent all-trans retinoic acid (RA) and chemotherapy. RA induces cell differentiation through retinoic acid receptor (RAR) transcription factors. Because redox mechanisms influence how readily transcription factors bind to DNA response elements (RARE), the impact of small molecule (E3330) inhibition of the redox regulatory protein, apurinic-apyrimidinic endonuclease/redox effector factor (APE1/Ref-1) on RAR DNA binding and function in RA-induced myeloid leukemia cell differentiation and apoptosis was investigated. The redox function of APE1 was studied using the small molecule inhibitor E3330 in HL-60 and PLB acute myeloid leukemia cells. Electrophoretic mobility shift assays (EMSA) were employed to determine effect of inhibitor on APE1/Ref-1 redox signaling function. Trypan blue assays, Annexin-V/PI and CD11b staining, and real time PCR analyses were employed to determine survival, apoptosis and differentiation status of cells in culture. RARα binds to its RARE in a redox-dependent manner mediated by APE1/Ref-1 redox regulation. Redox-dependent RAR-RARE binding is blocked by E3330, a small molecule redox inhibitor of APE1/Ref-1. Combination treatment of RA + E3330 results in a profound hypersensitivity of myeloid leukemia cells to RA-induced differentiation and apoptosis. Additionally, redox inhibition by E3330 results in enhanced RAR target gene, BLR-1, expression in myeloid leukemia cells. The redox function of APE1/Ref-1 regulates RAR binding to its DNA RAREs influencing the response of myeloid leukemia cells to RA-induced differentiation. Targeting of APE1/Ref-1 redox function may allow manipulation of the retinoid response with therapeutic implications.
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影响因子：
5.3
作者：
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通讯作者：
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影响因子：
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DOI：
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发表时间：
2009-12-11
影响因子：
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