肝癌是一个特别致命的癌症，但有效治疗晚期肝癌的治疗方案有限。多聚（ADP -核糖）聚合酶和组蛋白去乙酰化酶正在成为最有希望的目标靶位来治疗癌症，抑制多聚（ADP -核糖）聚合酶的敏感性依赖于同源重组缺乏。抑制组蛋白去乙酰化酶活性阻断同源重组的通路。在这里，我们对联合抑制两种酶活性能协同抑制肝癌生长这个假设做了实验，并定义了对酶抑制敏感性的分子水平的决定因素。我们发现，肝癌细胞对HDAC抑制剂异羟肟酸和PARP抑制剂olaparib的敏感性有不同差异，并且鉴定了称为snu-398和snu-449的一对细胞系，他们分别有对酶抑制剂敏感的耐药表型。SAHA和olaparib共同协同抑制SNU-398的增长,但不是snu – 449细胞,它有细胞凋亡增加和累积的不能修复的DNA损伤。多重证据证明肝纤维化/肝星状细胞激活可能是 细胞对两个酶抑制剂敏感性 的一种重要遗传因素,他也协调芳基碳氢化合物受体的激活或失活，环磷酸腺苷介导的信号通路参与细胞对SAHA和olaparib治疗反应。这些发现表明, 两酶抑制剂联合治疗可能是对敏感肝癌细胞的一个治疗方法,并发现这些新奇的分子决定因素可能最终引导PARP和HDAC抑制剂在临床的最佳应用。




Hepatocellular carcinoma (HCC) is a particularly lethal form of cancer, yet effective therapeutic options for advanced HCC are limited. The poly(ADP-ribose) polymerases (PARPs) and histone deacetylases (HDACs) are emerging to be among the most promising targets in cancer therapy, and sensitivity to PARP inhibition depends on homologous recombination (HR) deficiency and inhibition of HDAC activity blocks the HR pathway.Here, we tested the hypothesis that cotargeting both enzymatic activities could synergistically inhibit HCC growth and defined the molecular determinants of sensitivity to both enzyme inhibitors.We discovered that HCC cells have differential sensitivity to the HDAC inhibitor suberoy’lanilide hydroxamic acid (SAHA) and PARP inhibitor olaparib, and identified one pair of cell lines, termed SNU-398 and SNU-449, with sensitive versus resistant phenotype to both enzyme inhibitors, respectively.Coadministration of SAHA and olaparib synergistically inhibited the growth of SNU-398 but not SNU-449 cells, which was associated with increased apoptosis and accumulated unrepaired DNA damage.Multiple lines of evidence demonstrate that the hepatic fibrosis/hepatic stellate cell activation may be an important genetic determinant of cellular sensitivity to both enzymatic inhibitors, and coordinate activation or inactivation of the aryl hydrocarbon receptor (AhR) and cAMP-mediated signaling pathways are involved in cell response to SAHA and olaparib treatment.These findings suggest that combination therapy with both enzyme inhibitors may be a strategy for therapy of sensitive HCC cells, and identification of these novel molecular determinants may eventually guide the optimal use of PARP and HDAC inhibitors in the clinic.

点击下载 染色质修饰酶和多聚（ADP -核糖）聚合酶的靶位测定对肝癌生长的协同抑制作用