Aix Marseille Univ, UMR 911, Campus Santé Timone, Marseille F-13005, France.
Pancreatology. 2012 Mar-Apr;12(2):146-55. doi: 10.1016/j.pan.2012.02.013. Epub 2012 Feb 25.
In this study, the effect of LBH589 and trichostatin (TSA), a standard histone deacetylase inhibitor (HDACi) toward the growth of pancreatic cancer cell lines was studied. Thus, we examined for the first time, the HDAC family gene expression levels before and after drug treatment.
Several human pancreatic cancer cell lines (Panc-1, BxPC-3, SOJ-6) and a normal human pancreatic duct immortalized epithelial cell line (HPDE/E6E7) were used as target cells. The cell growth was measured by MTT assay, cell cycle alteration, membrane phosphatidylserine exposure, DNA fragmentation, mitochondrial membrane potential loss, RT-PCR and Western blots were done using standard methods. The effect of drugs on tumor growth in vivo was studied using subcutaneous xenograft model.
Except in the case of certain HDAC gene/tumor cell line couples: (SIRT1/HPDE-SOJ6/TSA- or LBH589-treated cells; LBH589-treated Panc-1 Cells; HDAC2/BxPC-3/LBH589-treated cells or TSA-treated SOJ-6-1 cells), there were no major significant changes of HDACs genes transcription in cells upon drug treatment. However, significant variation in HDACs and SIRTs protein expression levels could be seen among individual cell samples. The in vivo results showed that LBH589 formulation exhibited similar tumor reduction efficacy as the commercial drug gemcitabine.
Our data demonstrate that LBH589 induced the death of pancreatic tumor cell by apoptosis. In line with its in vitro activity, LBH589 achieved a significant reduction in tumor growth in BxPC-3 pancreatic tumor cell line subcutaneous xenograft mouse model. Furthermore, exploring the impact of LBH589 on HDACs encoding genes expression revealed for the first time that some of them, depending on the cell line considered, seem to be regulated during translation.
在这项研究中，研究了 LBH589 和曲古抑菌素 A（TSA），一种标准的组蛋白去乙酰化酶抑制剂（HDACi）对胰腺癌细胞系生长的影响。因此，我们首次检查了药物治疗前后 HDAC 家族基因表达水平。
使用几种人胰腺癌细胞系（Panc-1、BxPC-3、SOJ-6）和正常的人胰腺导管永生化上皮细胞系（HPDE/E6E7）作为靶细胞。通过 MTT 测定法测量细胞生长，改变细胞周期，膜磷脂酰丝氨酸暴露，DNA 片段化，线粒体膜电位丧失，使用标准方法进行 RT-PCR 和 Western blot。使用皮下异种移植模型研究药物对体内肿瘤生长的影响。
除了在某些 HDAC 基因/肿瘤细胞系偶对中（SIRT1/HPDE-SOJ6/TSA-或 LBH589 处理的细胞；LBH589 处理的 Panc-1 细胞；HDAC2/BxPC-3/LBH589 处理的细胞或 TSA 处理的 SOJ-6-1 细胞），药物处理后细胞中 HDACs 基因转录没有发生重大变化。然而，个别细胞样本中可以看到 HDACs 和 SIRTs 蛋白表达水平的显著变化。体内结果表明，LBH589 制剂表现出与商业药物吉西他滨相似的肿瘤减少功效。
我们的数据表明，LBH589 通过细胞凋亡诱导胰腺肿瘤细胞死亡。与体外活性一致，LBH589 使 BxPC-3 胰腺肿瘤细胞系皮下异种移植小鼠模型中的肿瘤生长显著减少。此外，探索 LBH589 对编码 HDACs 的基因表达的影响首次表明，其中一些基因，取决于所考虑的细胞系，在翻译过程中似乎受到调节。
