High PARP-1 expression predicts poor survival in acute myeloid leukemia and PARP-1 inhibitor and SAHA-bendamustine hybrid inhibitor combination treatment synergistically enhances anti-tumor effects.
High PARP-1 expression predicts poor survival in acute myeloid leukemia and PARP-1 inhibitor and SAHA-bendamustine hybrid inhibitor combination treatment synergistically enhances anti-tumor effects.
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PARP-1 高表达预示急性髓系白血病生存率较差，PARP-1 抑制剂和 SAHA-苯达莫司汀混合抑制剂联合治疗可协同增强抗肿瘤作用。
DOI：
10.1016/j.ebiom.2018.11.025
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发表时间：
2018-12
期刊：
影响因子：
11.1
通讯作者：
Jin J
中科院分区：
文献类型：
--
作者：
Li X;Li C;Jin J;Wang J;Huang J;Ma Z;Huang X;He X;Zhou Y;Xu Y;Yu M;Huang S;Yan X;Li F;Pan J;Wang Y;Yu Y;Jin J
PARP-1在DNA损伤修复中起着关键作用，并有助于癌症的进展。为了探讨PARP-1在急性髓系白血病（AML）中的作用，我们分析了PARP-1在AML中的表达及其与临床预后的关系。然后，我们研究了PARP抑制剂BMN 673（Talazoparib）与新型SAHA-苯达莫司汀杂合物NL 101的体外和体内疗效和机制。应用逆转录聚合酶链反应（RT-PCR）检测339例细胞遗传学正常的急性髓性白血病（CN-AML）患者外周血中PARP-1的表达。根据PARP-1的表达情况，对患者的临床特点及预后进行分组比较。在AML细胞和MV 4 -11的B-NSG小鼠异种移植模型中研究了BMN 673和NL 101的组合作用。我们发现PARP-1高表达组患者骨髓中的原始细胞（P = 0.003）和外周血中的白色细胞（WBC）（P = 0.008）水平较高，并且与更频繁的FLT 3-ITD突变相关（28.2% vs 17.3%，P = 0.031）。高表达组的总生存期（OS）和无事件生存期（EFS）明显短于低表达组（OS，P = 0.005和EFS，P = 0.004）。BMN 673与NL 101联合治疗AML具有较强的协同作用。联合用药可明显诱导细胞凋亡，使细胞周期阻滞于G2/M期。BMN 673和NL 101联合处理促进了DNA损伤。在体内，该组合有效地延缓了AML的发展并延长了生存期。PARP-1高表达预示CN-AML患者生存率低。PARP抑制剂BMN 673与SAHA-苯达莫司汀杂合物NL 101组合的协同效应提供了针对AML的新治疗策略。国家自然科学基金、浙江省重点创新团队。
PARP-1 plays a critical role in DNA damage repair and contributes to progression of cancer. To explore the role of PARP-1 in acute myeloid leukemia (AML), we analyzed the expression of PARP-1 in AML and its relation to the clinical prognosis. Then, we investigated the efficacy and mechanism of PARP inhibitor BMN673 (Talazoparib) combined with NL101, a novel SAHA-bendamustine hybrid in vitro and in vivo. The expression of PARP-1 in 339 cytogenetically normal AML (CN-AML) cases was evaluated using RT-PCR. According to the expression of PARP-1, the clinical characteristics and prognosis of the patients were grouped and compared. The combination effects of BMN673 and NL101 were studied in AML cells and B-NSG mice xenograft model of MV4-11. We found patients in high PARP-1 expression group had higher levels of blast cells in bone marrow (P = .003) and white blood cells (WBC) in peripheral blood (P = .008), and were associated with a more frequent FLT3-ITD mutation (28.2% vs 17.3%, P = .031). The overall survival (OS) and event free survival (EFS) of the high expression group were significantly shorter than those in the low expression group (OS, P = .005 and EFS, P = .004). BMN673 combined with NL101 had a strong synergistic effect in treating AML. The combination significantly induced cell apoptosis and arrested cell cycle in G2/M phase. Mechanistically, BMN673 and NL101 combinatorial treatment promoted DNA damage. In vivo, the combination effectively delayed the development of AML and prolonged survival. High PARP-1 expression predicts poor survival in CN-AML patients. The synergistic effects of PARP inhibitor BMN673 in combination with SAHA-bendamustine hybrid, NL101, provide a new therapeutic strategy against AML. National Natural Science Foundation of China and Zhejiang Provincial Key Innovation Team.
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影响因子：
19
作者：
Ceccaldi R;Rondinelli B;D'Andrea AD
通讯作者：
D'Andrea AD
影响因子：
3.8
作者：
Bi FF;Li D;Yang Q
通讯作者：
Yang Q
影响因子：
--
作者：
Bi FF;Li D;Yang Q
通讯作者：
Yang Q
影响因子：
16
作者：
Krishnakumar R;Kraus WL
通讯作者：
Kraus WL
苯达莫司汀和恩替司他的组合通过诱导细胞凋亡和 DNA 损伤反应协同抑制多发性骨髓瘤细胞的增殖。
影响因子：
9.7
作者：
Cai, Bo;Lyu, Hui;Huang, Jingcao;Wang, Shuiliang;Lee, Choon-Kee;Gao, Chunji;Liu, Bolin
通讯作者：
Liu, Bolin