Panobinostat induces apoptosis via production of reactive oxygen species and synergizes with topoisomerase inhibitors in cervical cancer cells.
Panobinostat induces apoptosis via production of reactive oxygen species and synergizes with topoisomerase inhibitors in cervical cancer cells.
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DOI：
10.1016/j.biopha.2016.10.057
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发表时间：
2016-12
期刊：
影响因子：
--
通讯作者：
Lubna Wasim;Madhu Chopra
中科院分区：
文献类型：
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作者：
Lubna Wasim;Madhu Chopra
宫颈癌是全世界妇女癌症相关死亡的第四大原因，也是发展中国家最常见的癌症。因此，寻找新的治疗方式是必要的。本研究旨在探讨泛组蛋白去乙酰化酶抑制剂帕比司他（panobinostat）单独及与拓扑异构酶抑制剂联合应用对宫颈癌细胞的作用。我们使用各种测定评估帕比司他对两种宫颈癌细胞系HeLa和SiHa的细胞活力、细胞凋亡、氧化应激和线粒体功能的影响。结果表明，帕比司他以剂量和时间依赖性方式降低宫颈癌细胞的活力;它将HeLa细胞阻滞在细胞周期的G 0/G1期，将SiHa细胞阻滞在细胞周期的G2/M期。帕比司他通过增加ROS产生和破坏线粒体膜电位诱导细胞凋亡。同时，抗凋亡基因Bcl-xL的表达减少，而CDK抑制剂p21和caspase-9的水平增加。帕比司他增加组蛋白H3的乙酰化，表明HDAC抑制。此外，与单独用帕比司他处理的细胞相比，帕比司他还显示出与拓扑异构酶抑制剂的协同效应，其通过增加的半胱天冬酶-3/7活性的活化介导。这些结果表明，使用组蛋白去乙酰化酶和拓扑异构酶抑制剂的联合治疗可能是一种有效的靶向治疗策略。
Cervical cancer is the fourth major cause of cancer-related deaths in women worldwide and is the most common cancer in developing countries. Therefore, a search for novel treatment modalities is warranted. The present study is designed to investigate the effect of pan histone deacetylase inhibitor, ‘panobinostat’, on cervical cancer cells alone and in combination with topoisomerase inhibitors. We assessed the effect of panobinostat on two cervical cancer cell lines, HeLa and SiHa, for cell viability, apoptosis, oxidative stress and mitochondrial function using various assays. The results indicate that panobinostat reduces the viability of cervical cancer cells in a dose- and time-dependent manner; it arrests HeLa cells in G0/G1 and SiHa cells in G2/M phase of the cell cycle. Panobinostat induced apoptosis through an increase in the ROS production and the disruption of mitochondrial membrane potential. Concomitantly the expression of anti-apoptotic gene Bcl-xL was reduced, while levels of CDK inhibitor p21 and caspase-9 were increased. Panobinostat increased the acetylation of histone H3 indicating HDAC inhibition. In addition, panobinostat also showed synergistic effect with topoisomerase inhibitors mediated by increased activation of caspase-3/7 activity compared to that in cells treated with panobinostat alone. These results suggest a combination therapy using inhibitors of histone deacetylase and topoisomerase together could hold the promise for an effective targeted therapeutic strategy.