Gene expression signature analysis identifies vorinostat as a candidate therapy for gastric cancer

• Published in: PloS one 2011-09, Vol.6 (9), p.e24662
• Main Authors: Claerhout, Sofie, Lim, Jae Yun, Choi, Woonyoung, Park, Yun-Yong, Kim, Kyounghyun, Kim, Sang-Bae, Lee, Ju-Seog, Mills, Gordon B, Cho, Jae Yong
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Apolipoprotein C-I - genetics; Apolipoprotein C-I - metabolism; Apoptosis; Biology; Biomarkers; Biotechnology; Blotting, Western; Cancer; Cancer genetics; Cancer research; Cancer therapies; Cancer treatment; Care and treatment; Cell death; Cell Line, Tumor; Chemical compounds; Chemotherapy; Chromobox Protein Homolog 5; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - metabolism; Colorectal cancer; Disease; DNA microarrays; Drug delivery; Drugs; Esophagus; Gastric cancer; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Genes; Genetic aspects; Group II Phospholipases A2 - genetics; Group II Phospholipases A2 - metabolism; Growth factors; Health aspects; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Humans; Hydroxamic Acids - pharmacology; In Vitro Techniques; Kinesins - genetics; Kinesins - metabolism; Medical prognosis; Medicine; Metastasis; Neuroblastoma; Oligonucleotide Array Sequence Analysis; Pancreatic cancer; Patients; Phagocytosis; Pharmacology; Signature analysis; Stomach cancer; Stomach Neoplasms - metabolism; Tumor cell lines; Vorinostat
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0024662

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. 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. 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.