Histone deacetylase inhibitors vorinostat and panobinostat induce G1 cell cycle arrest and apoptosis in multidrug resistant sarcoma cell lines.
Histone deacetylase inhibitors vorinostat and panobinostat induce G1 cell cycle arrest and apoptosis in multidrug resistant sarcoma cell lines.
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DOI：
10.18632/oncotarget.20460
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发表时间：
2017-09-29
期刊：
影响因子：
--
通讯作者：
Lohberger B
中科院分区：
文献类型：
--
作者：
Bernhart E;Stuendl N;Kaltenegger H;Windpassinger C;Donohue N;Leithner A;Lohberger B
滑膜肉瘤和高级别软骨肉瘤的特点是对常规细胞毒化疗缺乏反应，倾向于发展为肺转移，存活率低。该领域的研究优先考虑开发和扩大新的治疗方案，以应对不可切除或转移性疾病。使用组蛋白去乙酰化酶抑制剂（HDACi）的许多临床试验已经显示出作为用于治疗各种实体瘤的活性抗肿瘤剂的特异性功效。然而，到目前为止，尚未研究不同HDACi对滑膜和软骨肉瘤细胞的影响。在这项研究中，伏立诺他（SAHA）、帕比司他（LBH-589）和贝利司他（PXD 101）以时间和剂量依赖性方式降低滑膜肉瘤（SW-982）和软骨肉瘤（SW-1353）细胞的细胞活力，并将SW-982细胞阻滞在G1/S期。Western blot分析确定了负责细胞周期调节蛋白。此外，我们发现凋亡诱导caspase 3/7活性，caspase 3裂解，PARP裂解。在SW-1353细胞中，只有SAHA显示出相当的效果。值得注意的是，所有测试的HDACi与拓扑异构酶II抑制剂阿霉素在SW-1353软骨肉瘤细胞中具有协同作用，使细胞对化疗药物更敏感。我们的研究结果首次表明，SAHA和LBH-589降低了肉瘤细胞的生存力，并将其阻滞在G1/S检查点，同时还诱导细胞凋亡并增强化疗敏感性，特别是在软骨肉瘤细胞中。这些数据表明HDACi用于肉瘤治疗的令人兴奋的潜力。
Synovial sarcoma and high grade chondrosarcoma are characterized by their lack of response to conventional cytotoxic chemotherapy, the tendency to develop lung metastases, and low survival rates. Research within the field prioritizes the development and expansion of new treatment options for dealing with unresectable or metastatic diseases. Numerous clinical trials using histone deacetylases inhibitors (HDACi) have shown specific efficacy as an active antitumor agent for treating a variety of solid tumors. However, as of yet the effect of different HDACi on synovial- and chondrosarcoma cells has not been investigated. In this study, vorinostat (SAHA), panobinostat (LBH-589), and belinostat (PXD101) decreased cell viability of synovial sarcoma (SW-982) and chondrosarcoma (SW-1353) cells in a time- and dose dependent manner and arrested SW-982 cells in the G1/S phase. Western blot analysis determined the responsible cell cycle regulator proteins. In addition, we found apoptotic induction by caspase 3/7 activity, caspase 3 cleavage, and PARP cleavage. In SW-1353 cells only SAHA showed comparable effects. Noteworthy, all HDACi tested had synergistic effects with the topoisomerase II inhibitor doxorubicin in SW-1353 chondrosarcoma cells making the cells more sensitive to the chemotherapeutic drug. Our results show for the first time that SAHA and LBH-589 reduced viability of sarcoma cells and arrested them at the G1/S checkpoint, while also inducing apoptosis and enhancing chemotherapeutic sensitivity, especially in chondrosarcoma cells. These data demonstrate the exciting potential of HDACi for use in sarcoma treatment.
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影响因子：
--
作者：
Herrero-Ruiz J;Mora-Santos M;Giráldez S;Sáez C;Japón MA;Tortolero M;Romero F
通讯作者：
Romero F
影响因子：
4.5
作者：
Jo, Vickie Y.;Fletcher, Christopher D. M.
通讯作者：
Fletcher, Christopher D. M.
影响因子：
45.3
作者：
Chugh, R;Dunn, R;Baker, LH
通讯作者：
Baker, LH
组蛋白去乙酰化酶抑制剂 SAHA 对横纹肌肉瘤细胞的化疗增敏作用
影响因子：
9.7
作者：
Heinicke, Ulrike;Fulda, Simone
通讯作者：
Fulda, Simone
影响因子：
3.8
作者：
Kerl K;Ries D;Unland R;Borchert C;Moreno N;Hasselblatt M;Jürgens H;Kool M;Görlich D;Eveslage M;Jung M;Meisterernst M;Frühwald M
通讯作者：
Frühwald M