Downregulation of survivin and aurora A by histone deacetylase and RAS inhibitors: a new drug combination for cancer therapy
Downregulation of survivin and aurora A by histone deacetylase and RAS inhibitors: a new drug combination for cancer therapy
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DOI：
10.1002/ijc.25367
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发表时间：
2011-02-01
影响因子：
6.4
通讯作者：
Kloog, Yoel
中科院分区：
文献类型：
--
作者：
Biran, Anat;Brownstein, Michael;Kloog, Yoel
组蛋白去乙酰化酶（HDAC）抑制剂，如丙戊酸（VPA），构成一类新的抗癌剂，其引起乙酰化组蛋白的增加，从而恢复休眠的肿瘤抑制基因和与肿瘤细胞的细胞分化、细胞周期停滞或凋亡相关的其它基因的表达。Ras抑制剂法尼基硫代水杨酸（FTS，salirasib）在体外和体内减弱癌细胞增殖，并且在某些情况下诱导细胞死亡。FTS本身不诱导分化或完全生长停滞。VPA作为分化剂的上述活性表明，可能值得研究其与FTS协同组合的可能治疗潜力。在这里，我们研究了VPA和FTS的联合应用是否可以协同抑制表达致癌K-Ras（A549非小细胞肺癌细胞）、DLD 1（结肠癌细胞）或慢性活性野生型K-Ras和组成型活性B-Raf（ARO，甲状腺癌细胞）的癌细胞的增殖。结果表明，VPA和FTS联合治疗通过下调Ras并阻断Survivin和Aurora A的表达，协同降低了所有这些癌细胞系的增殖。这些变化，这是最明显的联合治疗后，导致有丝分裂危机，所反映的错误定位的染色体乘客复合体。因此，我们的研究结果表明，VPA和FTS的联合治疗可能会提供一个有前途的治疗方法来治疗上皮肿瘤。
Histone deacetylase (HDAC) inhibitors, such as valproic acid (VPA), constitute a novel class of anticancer agents that cause an increase in acetylated histones and thus restore the expression of dormant tumor-suppressor and other genes related to cell differentiation, cell-cycle arrest or apoptosis of tumor cells. The Ras inhibitor farnesylthiosalicylic acid (FTS, salirasib) attenuates cancer cell proliferation in vitro and in vivo and, under certain circumstances, induces cell death. FTS by itself does not induce differentiation or complete growth arrest. The abovementioned activity of VPA as a differentiation agent suggested that it might be worth investigating its possible therapeutic potential in synergistic combination with FTS. Here, we examined whether the combined application of VPA and FTS could synergistically inhibit the proliferation of cancer cells that express oncogenic K-Ras (A549 nonsmall-cell lung carcinoma cells), DLD1 (colon carcinoma cells) or chronically active wild-type K-Ras and constitutively active B-Raf (ARO, thyroid carcinoma cells). The results showed that combined treatment with VPA and FTS synergistically reduces proliferation in all of these cancer cell lines by downregulating Ras and blocking the expression of Survivin and Aurora A. These alterations, which were most pronounced following the combined treatment, led to a mitotic crisis, as reflected by mislocalization of the chromosomal passenger complex. Our findings thus demonstrate that combination therapy with VPA and FTS might offer a promising therapeutic approach to the treatment of epithelial tumors.