Treatment of nasopharyngeal carcinoma cells with the histone-deacetylase inhibitor abexinostat: cooperative effects with cis-platin and radiotherapy on patient-derived xenografts.
Treatment of nasopharyngeal carcinoma cells with the histone-deacetylase inhibitor abexinostat: cooperative effects with cis-platin and radiotherapy on patient-derived xenografts.
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DOI：
10.1371/journal.pone.0091325
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Busson P
中科院分区：
文献类型：
--
作者：
Gressette M;Vérillaud B;Jimenez-Pailhès AS;Lelièvre H;Lo KW;Ferrand FR;Gattolliat CH;Jacquet-Bescond A;Kraus-Berthier L;Depil S;Busson P
EBV 相关鼻咽癌 (NPC) 仍然引发严重的治疗问题。使用 5 个临床前 NPC 模型（包括 2 个患者来源的异种移植物（C15 和 C17））研究了组蛋白脱乙酰酶 (HDAC) 抑制剂 Abexinostat 的治疗潜力。使用 2 个 EBV 阴性（CNE1 和 HONE1）和 3 个 EBV 阳性 NPC 模型（C15、C17 和 C666-1），通过 MTT 和克隆形成试验，在体外评估 Abexinostat 单独使用或与顺铂或放射组合使用的细胞毒性。随后，以异种移植的形式使用3个EBV阳性模型来评估Abexinostat或Abexinostat与顺铂或放射组合的全身治疗的影响。在治疗的肿瘤中研究了几种已知受 HDAC 抑制剂和小病毒非编码 RNA EBER1 影响的细胞蛋白。 Abexinostat 与顺铂或放射联合使用的协同细胞毒性作用在每个 NPC 模型的体外得到了证实。当使用异种移植物时，Abexinostat 本身（12.5 mg/kg，BID，每周 4 天，持续 3 周）对 C17 具有显着的抗肿瘤作用。观察到顺铂（2 mg/kg，IP，第 3、10 和 17 天）和照射（1Gy）对 C15 和 C17 异种移植物的协同作用。同时在肿瘤组织中诱导了两种类型的生物学改变，尤其是在 C17 模型中：DNA 修复蛋白 RAD51 的消耗和小病毒 RNA EBER1 的更强的原位检测。总体而言，这些结果支持实施 Abexinostat 治疗鼻咽癌的 I/II 期临床试验。 RAD51 的消耗可能有助于 Abexinostat 与 DNA 损伤剂的协同作用。 RAD51 的减少与 EBER 1 检测的增强相结合可能有助于肿瘤反应的早期评估。
EBV-related nasopharyngeal carcinomas (NPCs) still raise serious therapeutic problems. The therapeutic potential of the histone-deacetylase (HDAC) inhibitor Abexinostat was investigated using 5 preclinical NPC models including 2 patient-derived xenografts (C15 and C17). The cytotoxicity of Abexinostat used either alone or in combination with cis-platin or irradiation was assessed in vitro by MTT and clonogenic assays using 2 EBV-negative (CNE1 and HONE1) and 3 EBV-positive NPC models (C15, C17 and C666-1). Subsequently, the 3 EBV-positive models were used under the form of xenografts to assess the impact of systemic treatments by Abexinostat or combinations of Abexinostat with cis-platin or irradiation. Several cell proteins known to be affected by HDAC inhibitors and the small viral non-coding RNA EBER1 were investigated in the treated tumors. Synergistic cytotoxic effects of Abexinostat combined with cis-platin or irradiation were demonstrated in vitro for each NPC model. When using xenografts, Abexinostat by itself (12.5 mg/kg, BID, 4 days a week for 3 weeks) had significant anti-tumor effects against C17. Cooperative effects with cis-platin (2 mg/kg, IP, at days 3, 10 and 17) and irradiation (1Gy) were observed for the C15 and C17 xenografts. Simultaneously two types of biological alterations were induced in the tumor tissue, especially in the C17 model: a depletion of the DNA-repair protein RAD51 and a stronger in situ detection of the small viral RNA EBER1. Overall, these results support implementation of phase I/II clinical trials of Abexinostat for the treatment of NPC. A depletion of RAD51 is likely to contribute to the cooperation of Abexinostat with DNA damaging agents. Reduction of RAD51 combined to enhanced detection of EBER 1 might be helpful for early assessment of tumor response.
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影响因子：
50.3
作者：
Fotheringham, Susan;Epping, Mirjam T.;La Thangue, Nicholas B.
通讯作者：
La Thangue, Nicholas B.
影响因子：
51.1
作者：
Chen, Lei;Hu, Chao-Su;Ma, Jun
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Ma, Jun
影响因子：
158.5
作者：
Bonner, JA;Harari, PM;Ang, KK
通讯作者：
Ang, KK
影响因子：
6.4
作者：
BUSSON, P;GANEM, G;TURSZ, T
通讯作者：
TURSZ, T
影响因子：
8.4
作者：
Jin, Y.;Ye, X.;Zhang, Y. P.
通讯作者：
Zhang, Y. P.