Combining PCI-24781, a Novel Histone Deacetylase Inhibitor, with Chemotherapy for the Treatment of Soft Tissue Sarcoma
Combining PCI-24781, a Novel Histone Deacetylase Inhibitor, with Chemotherapy for the Treatment of Soft Tissue Sarcoma
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DOI：
10.1158/1078-0432.ccr-08-2714
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发表时间：
2009-05-15
影响因子：
11.5
通讯作者：
Lev, Dina C.
中科院分区：
文献类型：
--
作者：
Lopez, Gonzalo;Liu, Juehui;Lev, Dina C.
目的：组蛋白去乙酰化酶抑制剂（HDACi）是一类有前途的新的抗癌治疗剂;然而，关于HDACi在软组织肉瘤（STS）中的活性知之甚少，STS是间充质来源恶性肿瘤的异质性队列。因此，我们研究了新的HDACi PCI-24781，单独/与常规化疗相结合，以确定其潜在的抗STS相关的影响和潜在的mechanisms involved.Experimental Design：免疫印迹被用来评估PCI-24781对组蛋白和非组蛋白蛋白乙酰化和潜在的下游靶点的表达的影响。利用基于细胞培养的测定来评估PCI-24781对STS细胞生长、细胞周期进展、细胞凋亡和化学敏感性的影响。定量逆转录-PCR，染色质免疫沉淀，和报告分析有助于阐明分子机制导致PCI-24781诱导的Rad 51抑制。结果：PCI-24781在体外具有明显的抗STS增殖活性，诱导S期细胞减少，G2/M期细胞阻滞，并增加细胞凋亡。联合化疗效果上级。PCI-24781诱导的Rad 51（DNA双链断裂同源重组修复的主要介质）减少可能是PCI-24781化学增敏的潜在机制。我们发现PCI-24781通过Rad 51近端启动子上的E2 F结合位点转录抑制Rad 51。虽然单剂PCI-24781 STS的生长和转移有适度的影响，显着的抑制，观察到当与chemotherapy.Conclusions相结合：根据这些研究结果，这种新的基于分子的组合可能适用于多个STS组织学亚型，并可能值得在人类STS临床试验中进行严格的评估。
Purpose: Histone deactylase inhibitors (HDACi) are a promising new class of anticancer therapeutics; however, little is known about HDACi activity in soft tissue sarcoma (STS), a heterogeneous cohort of mesenchymal origin malignancies. Consequently, we investigated the novel HDACi PCI-24781, alone/in combination with conventional chemotherapy, to determine its potential anti-STS-related effects and the underlying mechanisms involved.Experimental Design: Immunoblotting was used to evaluate the effects of PCI-24781 on histone and nonhistone protein acetylation and expression of potential downstream targets. Cell culture-based assays were utilized to assess the effects of PCI-24781 on STS cell growth, cell cycle progression, apoptosis, and chemosensitivity. Quantitative reverse transcription-PCR, chromatin immunoprecipitation, and reporter assays helped elucidate molecular mechanisms resulting in PCI-24781-induced Rad51 repression. The effect of PCI-24781, alone or with chemotherapy, on tumor and metastatic growth was tested in vivo using human STS xenograft models.Results: PCI-24781 exhibited significant anti-STS proliferative activity in vitro, inducing S phase depletion, G(2)/M cell cycle arrest, and increasing apoptosis. Superior effects were seen when combined with chemotherapy. A PCI-24781-induced reduction in Rad51, a major mediator of DNA double-strand break homologous recombination repair, was shown and may be a mechanism underlying PCI-24781 chemosensitization. We showed that PCI-24781 transcriptionally represses Rad51 through an E2F binding-site on the Rad51 proximal promoter. Although single-agent PCI-24781 had modest effects on STS growth and metastasis, marked inhibition was observed when combined with chemotherapy.Conclusions: In light of these findings, this novel molecular-based combination may be applicable to multiple STS histologic subtypes, and potentially merits rigorous evaluation in human STS clinical trials.