Ricolinostat, a selective HDAC6 inhibitor, shows anti-lymphoma cell activity alone and in combination with bendamustine.
Ricolinostat, a selective HDAC6 inhibitor, shows anti-lymphoma cell activity alone and in combination with bendamustine.
复制标题
DOI：
10.1007/s10495-017-1364-4
复制
发表时间：
2017-06
期刊：
影响因子：
--
通讯作者：
Pozzi S
中科院分区：
文献类型：
--
作者：
Cosenza M;Civallero M;Marcheselli L;Sacchi S;Pozzi S
组蛋白去乙酰化酶抑制剂（HDACis）是近年来发展起来的一类新型抗癌药物，其作用靶点主要是细胞周期和细胞凋亡。我们研究并解释了HDAC6抑制剂ricolinostat单独使用和与苯达莫司汀联合使用在淋巴瘤细胞系中的抗癌作用。MTT法检测细胞活力。流式细胞仪检测细胞凋亡、活性氧（ROS）产生、Bcl-2蛋白表达、细胞周期进程和微管蛋白表达。通过免疫印迹评估ricolinostat单独和组合对半胱天冬酶、PI3K/Akt、Bcl-2途径、ER应激和UPR的影响。Ricolinostat在作为单一药剂使用时显示抗淋巴瘤活性，并且其诱导细胞凋亡的能力在淋巴瘤细胞系中被苯达莫司汀协同增强。联合用药可使G0/G1期和S期细胞比例降低，"亚G0/G1"峰增加。这种协同作用伴随着活性氧的增加，caspase-8、-9、-3的激活，PARP的裂解以及Bcl-2蛋白家族的调节。此外，暴露于ricolinostat诱导α-微管蛋白的乙酰化水平，苯达莫司汀未进一步改变其程度。最后，ricolinostat/苯达莫司汀的细胞凋亡作用可能通过对微管稳定的相应作用介导。我们的数据表明，ricolinostat联合苯达莫司汀可能是一种新的组合，有可能用作淋巴瘤的抗肿瘤药物。本文的在线版本（doi：10.1007/s10495 - 017 - 1364 - 4）包含补充材料，可供授权用户使用。
Histone deacetylase inhibitors (HDACis) have emerged as a new class of anticancer agents, targeting the biological process including cell cycle and apoptosis. We investigated and explained the anticancer effects of an HDAC6 inhibitor, ricolinostat alone and in combination with bendamustine in lymphoma cell lines. Cell viability was measured by MTT assay. Apoptosis, reactive oxygen species (ROS) generation, Bcl-2 protein expression, cell cycle progression and tubuline expression were determined by flow cytometry. The effects of ricolinostat alone and in combination on the caspases, PI3K/Akt, Bcl-2 pathways, ER stress and UPR were assessed by immunoblotting. Ricolinostat shows anti lymphoma activity when used as single agent and its capability to induce apoptosis is synergistically potentiated by the bendamustine in lymphoma cell lines. Drug combination reduced the proportion of cells in the G0/G1 and S phases and caused an increase of “sub-G0/G1” peak. The synergistic effect accompanied with the increased ROS, activation of caspase-8, -9, and -3, the cleavage of PARP and modulated by Bcl-2 proteins family. In addition, the exposure of ricolinostat induced the acetylation level of α-tubulin, the extend of which was not further modified by bendamustine. Finally, the apoptosis effect of ricolinostat/bendamustine may be mediated by a corresponding effect on microtubule stabilization. Our data suggest that ricolinostat in combination with bendamustine may be a novel combination with potential for use as an antitumor agent in lymphoma. The online version of this article (doi:10.1007/s10495-017-1364-4) contains supplementary material, which is available to authorized users.