Institute of Biomedicine and Molecular Immunology Alberto Monroy, National Research Council (CNR), Palermo, Italy.
PLoS One. 2013 Jun 12;8(6):e65569. doi: 10.1371/journal.pone.0065569. Print 2013.
Molecular targeted therapy has shown promise as a treatment for advanced hepatocellular carcinoma (HCC). Sorafenib, a multikinase inhibitor, recently received FDA approval for the treatment of advanced HCC. However, although sorafenib is well tolerated, concern for its safety has been expressed. Celecoxib (Celebrex®) is a selective cyclooxygenase-2 (COX-2) inhibitor which exhibits antitumor effects in human HCC cells. The present study examined the interaction between celecoxib and sorafenib in two human liver tumor cell lines HepG2 and Huh7. Our data showed that each inhibitor alone reduced cell growth and the combination of celecoxib with sorafenib synergistically inhibited cell growth and increased apoptosis. To better understand the molecular mechanisms underlying the synergistic antitumor activity of the combination, we investigated the expression profile of the combination-treated liver cancer cell lines using microarray analysis. Combination treatment significantly altered expression levels of 1,986 and 2,483 transcripts in HepG2 and Huh7 cells, respectively. Genes functionally involved in cell death, signal transduction and regulation of transcription were predominantly up-regulated, while genes implicated in metabolism, cell-cycle control and DNA replication and repair were mainly down-regulated upon treatment. However, combination-treated HCC cell lines displayed specificity in the expression and activity of crucial factors involved in hepatocarcinogenesis. The altered expression of some of these genes was confirmed by semi-quantitative and quantitative RT-PCR and by Western blotting. Many novel genes emerged from our transcriptomic analyses, and further functional analyses may determine whether these genes can serve as potential molecular targets for more effective anti-HCC strategies.
分子靶向治疗已被证明是治疗晚期肝细胞癌（HCC）的一种有前途的方法。索拉非尼（Sorafenib）是一种多激酶抑制剂，最近获得 FDA 批准用于治疗晚期 HCC。然而，尽管索拉非尼具有良好的耐受性，但人们对其安全性表示关注。塞来昔布（Celecoxib）（西乐葆®）是一种选择性环氧化酶-2（COX-2）抑制剂，在人 HCC 细胞中具有抗肿瘤作用。本研究在两种人肝癌细胞系 HepG2 和 Huh7 中研究了塞来昔布与索拉非尼之间的相互作用。我们的数据表明，每种抑制剂单独使用均可降低细胞生长，而塞来昔布与索拉非尼联合使用则协同抑制细胞生长并增加细胞凋亡。为了更好地理解联合治疗协同抗肿瘤活性的分子机制，我们使用微阵列分析研究了联合治疗肝癌细胞系的表达谱。联合治疗显著改变了 HepG2 和 Huh7 细胞中 1986 和 2483 个转录本的表达水平。功能上涉及细胞死亡、信号转导和转录调控的基因主要上调，而涉及代谢、细胞周期控制和 DNA 复制和修复的基因主要下调。然而，联合治疗的 HCC 细胞系在参与肝癌发生的关键因素的表达和活性方面表现出特异性。一些基因的表达变化通过半定量和定量 RT-PCR 和 Western blot 得到了证实。我们的转录组分析中出现了许多新的基因，进一步的功能分析可能确定这些基因是否可以作为更有效的抗 HCC 策略的潜在分子靶点。
