Identification of genes related to a synergistic effect of taxane and suberoylanilide hydroxamic acid combination treatment in gastric cancer cells

Hyun Chang; Sun Young Rha; Hei-Cheul Jeung; Jae-Jun Jung; Tae Soo Kim; Ho Jeong Kwon; Byung Soo Kim; Hyun Cheol Chung

doi:10.1007/s00432-010-0849-0

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Identification of genes related to a synergistic effect of taxane and suberoylanilide hydroxamic acid combination treatment in gastric cancer cells

Authors: Hyun Chang ; Sun Young Rha ; Hei-Cheul Jeung ; Jae-Jun Jung ; Tae Soo Kim ; Ho Jeong Kwon ; Byung Soo Kim ; Hyun Cheol Chung

Citation: JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY, Vol.136(12) : 1901-1913, 2010

Journal Title: JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY

ISSN: 0171-5216

Issue Date: 2010

MeSH: Algorithms ; Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Cell Line ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival ; Cluster Analysis ; Dose-Response Relationship, Drug ; Drug Synergism ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Hydroxamic Acids/administration & dosage ; Hydroxamic Acids/pharmacology* ; Inhibitory Concentration 50 ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Stomach Neoplasms/drug therapy* ; Stomach Neoplasms/genetics ; Stomach Neoplasms/pathology ; Taxoids/administration & dosage ; Taxoids/pharmacology* ; Xenograft Model Antitumor Assays

Keywords: Suberoylanilide hydroxamic acid ; Taxane ; Combination chemotherapy ; Chemosensitivity ; Biological marker ; Stomach neoplasms

Abstract: PURPOSE: We evaluated the cytotoxic effects of combining suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, with taxanes in human gastric cancer cell lines and assessed the pre-treatment difference of gene expression to identify genes that could potentially mediate the cytotoxic response.

METHODS: Gastric cancer cell lines were treated with SAHA and paclitaxel or docetaxel, and the synergistic interaction between the drugs was evaluated in vitro using the combination index (CI) method. We performed significance analysis of microarray (SAM) to identify chemosensitivity-related genes in gastric cancer cell lines that were concomitantly treated with SAHA and taxane. We generated a correlation matrix between gene expression and CI values to identify genes whose expression correlated with a combined effect of taxanes and SAHA.

RESULTS: Combination treatment with taxane and SAHA had a synergistic cytotoxic effect against taxane-resistant gastric cancer cells. We identified 49 chemosensitivity-related genes via SAM analysis. Among them, nine common genes (SLIT2, REEP2, EFEMP2, CDC42SE1, FSD1, POU1F1, ZNF79, ETNK1, and DOCK5) were extracted from the subsequent correlation matrix analysis.

CONCLUSIONS: The combination of taxane and SAHA could be efficacious for the treatment of gastric cancer. The genes that were related to the synergistic response to taxane and SAHA could serve as surrogate biomarkers to predict the therapeutic response in gastric cancer patients.