Division of Cancer Medicine, Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
PLoS One. 2011;6(9):e24662. doi: 10.1371/journal.pone.0024662. Epub 2011 Sep 9.
Gastric cancer continues to be one of the deadliest cancers in the world and therefore identification of new drugs targeting this type of cancer is thus of significant importance. The purpose of this study was to identify and validate a therapeutic agent which might improve the outcomes for gastric cancer patients in the future.
METHODOLOGY/PRINCIPAL FINDINGS: Using microarray technology, we generated a gene expression profile of human gastric cancer-specific genes from human gastric cancer tissue samples. We used this profile in the Broad Institute's Connectivity Map analysis to identify candidate therapeutic compounds for gastric cancer. We found the histone deacetylase inhibitor vorinostat as the lead compound and thus a potential therapeutic drug for gastric cancer. Vorinostat induced both apoptosis and autophagy in gastric cancer cell lines. Pharmacological and genetic inhibition of autophagy however, increased the therapeutic efficacy of vorinostat, indicating that a combination of vorinostat with autophagy inhibitors may therapeutically be more beneficial. Moreover, gene expression analysis of gastric cancer identified a collection of genes (ITGB5, TYMS, MYB, APOC1, CBX5, PLA2G2A, and KIF20A) whose expression was elevated in gastric tumor tissue and downregulated more than 2-fold by vorinostat treatment in gastric cancer cell lines. In contrast, SCGB2A1, TCN1, CFD, APLP1, and NQO1 manifested a reversed pattern.
CONCLUSIONS/SIGNIFICANCE: We showed that analysis of gene expression signature may represent an emerging approach to discover therapeutic agents for gastric cancer, such as vorinostat. The observation of altered gene expression after vorinostat treatment may provide the clue to identify the molecular mechanism of vorinostat and those patients likely to benefit from vorinostat treatment.
胃癌仍然是世界上最致命的癌症之一，因此鉴定针对这种癌症的新药具有重要意义。本研究的目的是鉴定和验证一种治疗剂，以期未来能改善胃癌患者的预后。
方法/主要发现：我们使用微阵列技术从人胃癌组织样本中生成了人类胃癌特异性基因的基因表达谱。我们将该图谱用于 Broad Institute 的 Connectivity Map 分析，以鉴定胃癌的候选治疗化合物。我们发现组蛋白去乙酰化酶抑制剂伏立诺他是主要化合物，因此是胃癌的潜在治疗药物。伏立诺他诱导胃癌细胞系发生凋亡和自噬。然而，自噬的药理学和遗传学抑制增加了伏立诺他的治疗效果，这表明伏立诺他与自噬抑制剂的联合治疗可能更有益。此外，胃癌的基因表达分析鉴定了一组基因（ITGB5、TYMS、MYB、APOC1、CBX5、PLA2G2A 和 KIF20A），其在胃癌肿瘤组织中表达升高，而在胃癌细胞系中经伏立诺他处理后下调超过 2 倍。相比之下，SCGB2A1、TCN1、CFD、APLP1 和 NQO1 则呈现相反的模式。
结论/意义：我们表明，基因表达谱分析可能代表一种发现胃癌治疗剂的新兴方法，例如伏立诺他。伏立诺他治疗后基因表达的改变可能为鉴定伏立诺他的分子机制以及那些可能从伏立诺他治疗中获益的患者提供线索。
