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

BACKGROUND: 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 mechan...

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Detalles Bibliográficos
Autores principales: Li, Xia, Li, Chenying, Jin, Jingrui, Wang, Jinghan, Huang, Jiansong, Ma, Zhixin, Huang, Xin, He, Xiao, Zhou, Yile, Xu, Yu, Yu, Mengxia, Huang, Shujuan, Yan, Xiao, Li, Fenglin, Pan, Jiajia, Wang, Yungui, Yu, Yongping, Jin, Jie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
Materias:
Research paper
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306376/
https://www.ncbi.nlm.nih.gov/pubmed/30472087
http://dx.doi.org/10.1016/j.ebiom.2018.11.025
Descripción
Sumario:BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUND: National Natural Science Foundation of China and Zhejiang Provincial Key Innovation Team.

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