Targeting HDAC with a novel inhibitor effectively reverses paclitaxel resistance in non-small cell lung cancer via multiple mechanisms.
Targeting HDAC with a novel inhibitor effectively reverses paclitaxel resistance in non-small cell lung cancer via multiple mechanisms.
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使用新型抑制剂靶向 HDAC 可通过多种机制有效逆转非小细胞肺癌中的紫杉醇耐药性。
DOI：
10.1038/cddis.2015.328
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发表时间：
2016-01-21
影响因子：
9
通讯作者：
Wu C
中科院分区：
文献类型：
--
作者：
Wang L;Li H;Ren Y;Zou S;Fang W;Jiang X;Jia L;Li M;Liu X;Yuan X;Chen G;Yang J;Wu C
紫杉醇化疗可显著降低大多数晚期非小细胞肺癌（NSCLC）患者的肿瘤负荷。然而，获得性耐药性限制了其临床应用。在这里，我们证明了组蛋白去乙酰化酶（HDAC）在紫杉醇耐药的NSCLC细胞中被激活，并且其激活在体外和体内促进紫杉醇耐药的NSCLC细胞的增殖和肿瘤发生。相比之下，HDAC 1（HDAC的主要亚型）的敲除在体外使耐药细胞对紫杉醇敏感。此外，我们观察到HDAC 1的过表达与p21（一种已知的HDAC靶点）的下调有关，在接受紫杉醇治疗的晚期NSCLC患者中，HDAC 1的过表达预测了化疗耐药性和不良结局。此外，我们还鉴定了一种新的HDAC抑制剂SNOH-3，其抑制HDAC的表达和活性，诱导细胞凋亡，并抑制细胞迁移，侵袭和血管生成。值得注意的是，用SNOH-3和紫杉醇的共治疗通过抑制HDAC活性克服紫杉醇抗性，导致在体外和临床前模型中诱导细胞凋亡和抑制血管生成。总之，我们的数据证明了HDAC在紫杉醇耐药NSCLC中的作用，并为克服紫杉醇获得性耐药提供了一种有前景的治疗策略。
Chemotherapy paclitaxel yields significant reductions in tumor burden in the majority of advanced non-small cell lung cancer (NSCLC) patients. However, acquired resistance limits its clinical use. Here we demonstrated that the histone deacetylase (HDAC) was activated in paclitaxel-resistant NSCLC cells, and its activation promoted proliferation and tumorigenesis of paclitaxel-resistant NSCLC cells in vitro and in vivo. By contrast, knockdown of HDAC1, a primary isoform of HDAC, sensitized resistant cells to paclitaxel in vitro. Furthermore, we observed that overexpression of HDAC1 was associated with the downregulation of p21, a known HDAC target, in advanced NSCLC patients with paclitaxel treatment, and predicted chemotherapy resistance and bad outcome. In addition, we also identified a novel HDACs inhibitor, SNOH-3, which inhibited HDAC expression and activity, induced cell apoptosis, and suppressed cell migration, invasion and angiogenesis. Notably, co-treatment with SNOH-3 and paclitaxel overcome paclitaxel resistance through inhibiting HDAC activity, leading to the induction of apoptosis and suppression of angiogenesis in vitro and in preclinical model. In summary, our data demonstrate a role of HDAC in paclitaxel-resistant NSCLC and provide a promising therapeutic strategy to overcome paclitaxel-acquired resistance.