Department of Biochemistry and Molecular Biology, George Washington University, Washington, DC, USA.
Hepatology. 2012 Jun;55(6):1840-51. doi: 10.1002/hep.25566.
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 suberoylanilide 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 cyclic adenosine monophosphate (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.
肝细胞癌（HCC）是一种特别致命的癌症形式，但晚期 HCC 的有效治疗选择有限。聚（ADP-核糖）聚合酶（PARPs）和组蛋白去乙酰化酶（HDACs）在癌症治疗中被认为是最有前途的靶点之一，而对 PARP 抑制的敏感性取决于同源重组（HR）缺陷，抑制 HDAC 活性会阻断 HR 途径。在这里，我们测试了同时靶向这两种酶活性是否可以协同抑制 HCC 生长的假设，并确定了对这两种酶抑制剂敏感的分子决定因素。我们发现 HCC 细胞对 HDAC 抑制剂 suberoylanilide hydroxamic acid（SAHA）和 PARP 抑制剂 olaparib 的敏感性不同，并且分别鉴定了一对对两种酶抑制剂具有敏感表型和耐药表型的细胞系，称为 SNU-398 和 SNU-449。SAHA 和 olaparib 的联合给药协同抑制 SNU-398 细胞的生长，但不抑制 SNU-449 细胞的生长，这与凋亡增加和未修复的 DNA 损伤积累有关。多项证据表明，肝纤维化/肝星状细胞激活可能是细胞对两种酶抑制剂敏感性的一个重要遗传决定因素，芳烃受体（AhR）和环腺苷酸（cAMP）介导的信号通路的协调激活或失活参与细胞对 SAHA 和 olaparib 治疗的反应。
这些发现表明，两种酶抑制剂的联合治疗可能是治疗敏感 HCC 细胞的一种策略，并且这些新的分子决定因素的鉴定最终可能指导 PARP 和 HDAC 抑制剂在临床上的最佳使用。
