DEVELOPMENT OF NEW CANCER THERAPY USING HISTONE DEACETHYLASE INHIBITORS

1. 乙酰化肽HDAC抑制剂具有一个模拟乙酰化赖氨酸的核心结构域，并直接与HDAC结合。因此，我们探讨了携带乙酰化赖氨酸的肽是否可以抑制HDAC并在癌细胞中引入凋亡。到目前为止，我们的几种肽对HDAC的作用还不够。我们现在正在煎炸其他肽。HDAC抑制剂介导的癌症治疗HDAC抑制剂单独引入多种癌细胞的凋亡。这些药物是很有希望的抗癌药物。然而，I期临床试验显示有一些不良反应，因此我们应该考虑如何减少给药剂量。在这方面，我们正在研究它们的联合治疗。到目前为止，我们发现HDAC抑制剂通过一些技术可以非常有效。我们现在正在准备新的手稿，并且已经提交了这个专利。我们的数据有力地表明，我们的技术可以减少它们抗癌活性所需的剂量。用报告基因法检测HAT过表达的生物学效应我们将p300或cbp表达载体转染到几种肿瘤细胞中。使用荧光素酶报告试验，我们发现它们的转录激活有一些差异。特别是，这两个基因都强烈激活AP-1转录。这强烈提示p300和CBP与MEK/ERK通路紧密相关。因此，我们研究这一机制。

1. Biological effects of aceylated peptidesHDAC inhibitors have a core domain which mimicks acetylated lysines, and bind to HDAC directly. We thus explored whether peptides carrying acetylated lysines can inhibit HDAC and introduce apoptosis in cancer cells. So far, our several peptides cannot have sufficient effects on HDAC. We are now frying other peptides.2. HDAC inhibitor-mediated cancer therapyHDAC inhibitors alone introduce apoptosis in a variety of carcinoma cells. These drugs are promising anticancer agents. However, phase I clinical trial revealed that there are some adverse effects and thus we should consider how their administration doses are reduced. In this regard, we are now investigating their combination therapy. To date, we found that HDAC inhibitors can be strongly effective with some technique. We are now preparing a new manuscript and have already submitted this patent. Our data strongly suggest that our technique can reduce required doses for their anticancer activity.3. Biological effect of HAT overexpressoin using reporter assaysWe transfected p300 or CBP-expression vectors into several cancer cells. Using a luciferase-reporter assay, we found that there are some difference in their transcriptional activation. Especially, both genes strongly activate AP-1 transcription. This strongly suggest that p300 and CBP are tightly linked to MEK/ERK pathway. We thus investigating this mechanism.