2-Bromopalmitate targets retinoic acid receptor alpha and overcomes all-trans retinoic acid resistance of acute promyelocytic leukemia.
2-Bromopalmitate targets retinoic acid receptor alpha and overcomes all-trans retinoic acid resistance of acute promyelocytic leukemia.
复制标题
2-溴棕榈酸酯靶向视黄酸受体α并克服急性早幼粒细胞白血病的全反式视黄酸耐药性
DOI：
10.3324/haematol.2018.191916
复制
发表时间：
2019-01
期刊：
影响因子：
10.1
通讯作者：
Chen GQ
中科院分区：
文献类型：
--
作者：
Lu Y;Yan JS;Xia L;Qin K;Yin QQ;Xu HT;Gao MQ;Qu XN;Sun YT;Chen GQ
白血病细胞对脂肪酸氧化的依赖性已在最近的研究中得到证实。因此，脂肪酸氧化的药理学抑制在抑制白血病中显示出显著的效果。2-溴铝酸酯是棕榈酸类似物，最初被认为是脂肪酸氧化的抑制剂，最近被认为是蛋白质棕榈酰化的抑制剂。然而，2-溴铝酸盐对白血病及其细胞靶点的影响尚不清楚。在此，我们在培养细胞系、可移植小鼠模型和原代母细胞中发现，2-溴铝酸盐与全反式维甲酸在急性早幼粒细胞白血病中具有协同分化诱导作用。此外，2-溴铝酸盐克服了全反式维甲酸耐药细胞和白血病小鼠的全反式维甲酸耐药。在机制上，2-溴铝酸酯共价结合维甲酸受体α (RARα)的半胱氨酸105和半胱氨酸174，并在全反式维甲酸存在下稳定RARα蛋白，而全反式维甲酸可诱导RARα降解，从而增强RARα靶基因的转录。两种半胱氨酸的突变在很大程度上消除了2-溴铝酸酯对全反式维甲酸诱导分化的协同作用，表明2-溴铝酸酯通过结合RARα促进全反式维甲酸诱导的分化。以全反式维甲酸为基础的方案，包括三氧化二砷或化疗，作为急性早幼粒细胞白血病的首选治疗方法，会诱发不良事件和不可逆的耐药性。我们期望全反式维甲酸与2-溴铝酸酯联合治疗急性早幼粒细胞白血病，特别是克服复发急性早幼粒细胞白血病患者的全反式维甲酸耐药，是一种有前景的治疗策略。
Fatty acid oxidation dependency of leukemia cells has been documented in recent studies. Pharmacologic inhibition of fatty acid oxidation, thereby, displays significant effects in suppressing leukemia. 2-Bromopalmitate, a palmitate analogue, was initially identified as an inhibitor of fatty acid oxidation, and recently recognized as an inhibitor of protein palmitoylation. However, the effects of 2-Bromopalmitate on leukemia and its cellular targets remain obscure. Herein, we discover in cultured cell lines, a transplantable mouse model, and primary blasts that 2-Bromopalmitate presents synergistic differentiation induction with all-trans retinoic acid in acute promyelocytic leukemia. Moreover, 2-Bromopalmitate overcomes all-trans retinoic acid resistance in all-trans retinoic acid-resistant cells and leukemic mice. Mechanistically, 2-Bromopalmitate covalently binds at cysteine 105 and cysteine 174 of retinoic acid receptor alpha (RARα) and stabilizes RARα protein in the presence of all-trans retinoic acid which is known to induce RARα degradation, leading to enhanced transcription of RARα-target genes. Mutation of both cysteines largely abrogates the synergistic effect of 2-Bromopalmitate on all-trans retinoic acid-induced differentiation, demonstrating that 2-Bromopalmitate promotes all-trans retinoic acid-induced differentiation through binding RARα. All-trans retinoic acid-based regimens including arsenic trioxide or chemotherapy, as preferred therapy for acute promyelocytic leukemia, induce adverse events and irreversible resistance. We expect that combining all-trans retinoic acid with 2-Bromopalmitate would be a promising therapeutic strategy for acute promyelocytic leukemia, especially for overcoming all-trans retinoic acid resistance of relapsed acute promyelocytic leukemia patients.
登录
查看更多内容
影响因子：
3.7
作者：
Chendamarai E;Ganesan S;Alex AA;Kamath V;Nair SC;Nellickal AJ;Janet NB;Srivastava V;Lakshmi KM;Viswabandya A;Abraham A;Aiyaz M;Mullapudi N;Mugasimangalam R;Padua RA;Chomienne C;Chandy M;Srivastava A;George B;Balasubramanian P;Mathews V
通讯作者：
Mathews V
影响因子：
5.1
作者：
Chen, Xueran;Du, Zhaoxia;Hao, Aijun
通讯作者：
Hao, Aijun
影响因子：
4
作者：
Davda D;El Azzouny MA;Tom CT;Hernandez JL;Majmudar JD;Kennedy RT;Martin BR
通讯作者：
Martin BR
影响因子：
4.1
作者：
CHASE, JFA;TUBBS, PK
通讯作者：
TUBBS, PK
影响因子：
20.3
作者：
Gianni, M;Calzi, ML;Garattini, E
通讯作者：
Garattini, E