HDAC as a Therapeutic Target for Treatment of Endometrial Cancers
HDAC as a Therapeutic Target for Treatment of Endometrial Cancers
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HDAC 作为治疗子宫内膜癌的治疗靶点
DOI：
10.2174/13816128113199990528
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发表时间：
2014-04-01
影响因子：
3.1
通讯作者：
Li, Jinping
中科院分区：
文献类型：
--
作者：
Ren, Juan;Zhang, Jia;Li, Jinping
越来越多的证据表明，表观遗传变化，如启动子特异性DNA超甲基化和组蛋白去乙酰化，导致肿瘤抑制基因沉默，并有助于恶性转化。用HDAC抑制剂治疗癌细胞可以重新激活沉默基因的表达，阻断细胞周期，并诱导细胞凋亡。在癌细胞培养物中的体外实验和使用小鼠xynograft模型的体内研究已经表明，HDAC抑制剂提供有效的抗癌作用。临床试验已导致批准SAHA（伏立诺他）用于治疗淋巴瘤。子宫内膜癌是女性生殖道最常见的恶性肿瘤。EC以广泛的表观遗传学改变而闻名，包括HDAC和DNMT酶的过表达，以及DNA修复基因如MLH1，肿瘤抑制基因PTEN和孕酮受体的频繁表观遗传学沉默，这表明这种类型的癌症对HDAC抑制剂的潜在高敏感性。事实上，许多实验室使用各种模型进行的研究表明，HDAC抑制剂是子宫内膜癌有希望的化疗试剂。本文综述了这些研究的结果，重点是提供新药物的最新发现。背景信息HDAC表达EC，HDAC抑制剂的特点是基于它们的相关性，我们关注的主题。HDAC抑制剂与放射治疗和其他常规治疗试剂的联合应用也进行了讨论。
Accumulating evidence suggested that epigenetic changes such as promoter-specific DNA hypermethylation and histone deacetylation cause tumor suppressor gene silencing and contribute to malignant transformation. Treatment of cancer cells with HDAC inhibitors can reactivate the expression of silenced genes, block the cell cycle, and induce cell apoptosis. In vitro experiments in cancer cell cultures and in vivo studies using mouse xynograft model have shown that HDAC inhibitors deliver potent anti-cancer effects. Clinical trials have led to approval of SAHA (Vorinostat) for treatment of lymphoma. Endometrial cancer (EC) is the most frequent malignancy in women's reproductive tract. EC is known for extensive epigenetic alterations, including overexpression of HDAC and DNMT enzymes, and the frequent epigenetic silencing of DNA repair genes such as MLH1, tumor suppressor genes PTEN, and progesterone receptor, which suggests a potentially high sensitivity of this type of cancer to HDAC inhibitors. Indeed, studies from many laboratories using various models have shown that HDAC inhibitors are promising chemotherapy reagents for endometrial cancers. This review summarizes the results from these studies, with an emphasis to provide an update on the new findings from new drugs. Background information on HDAC expression in EC, and features of HDAC inhibitors are presented based on their relevance to our focused topic. The combined application of HDAC inhibitors with radiation therapy and other conventional therapeutic reagents are also discussed.