title: Suberoylanilide hydroxamic acid enhances the antitumor activity of oxaliplatin by reversing the oxaliplatin‑induced Src activation in gastric cancer cells.
abstract: Oxaliplatin and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA), also known as vorinostat, are potent antitumor agents. The aim of this study was to investigate the effect of SAHA on the antitumor efficacy of oxaliplatin in gastric cancer and the interaction between oxaliplatin and SAHA. Cell growth inhibition was evaluated using Cell Counting Kit‑8 and colony formation assays. Xenografts established in nude mice were used to assess tumor growth in vivo. Western blot analysis was used to detect the expression of acetyl‑histone H3, phosphorylated histone H2AX (γH2AX), B‑cell lymphoma 2 (Bcl‑2), cleaved caspase‑3, cleaved poly (ADP‑ribose) polymerase (PARP), phosphorylated- (p-)Src, Src, Akt and p‑Akt in gastric cancer cells. The in vitro growth of SGC‑7901, Hs746T and MKN28 gastric cancer cells was found to be dose‑dependently inhibited by oxaliplatin and SAHA. Furthermore, combined treatment was observed to be more effective in inhibiting cancer cell growth and colony formation than monotherapy. Similar effects were found in the xenografts. A positive interaction was identified between oxaliplatin and SAHA (between‑subject effects of oxaliplatin and SAHA, P<0.001). In addition, combined exposure to oxaliplatin and SAHA increased γH2AX expression and decreased Bcl‑2 expression. The expression of cleaved caspase‑3 and PARP was also increased with combination treatment. Oxaliplatin‑induced Src phosphorylation was detected in gastric cancer cells, as we have previously reported. However, this effect was inhibited by SAHA. The oxaliplatin‑induced Src phosphorylation was not impaired with Akt inhibition. In conclusion, oxaliplatin and SAHA exhibited a positive interaction when used in combination and were found to suppress gastric cancer cell survival and growth. The reversal of oxaliplatin‑induced Src activation may be responsible for this positive interaction.
authors.affiliation: Department of Surgery, Shanghai Institute of Digestive Surgery, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Chenfei
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Surgery, Shanghai Institute of Digestive Surgery, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ji
authors.affiliation: Department of Surgery, Shanghai Institute of Digestive Surgery, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Shi
authors.affiliation: Department of Surgery, Shanghai Institute of Digestive Surgery, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Surgery, Shanghai Institute of Digestive Surgery, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Yingyan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Surgery, Shanghai Institute of Digestive Surgery, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Bingya
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Surgery, Shanghai Institute of Digestive Surgery, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Zhenggang
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Surgery, Shanghai Institute of Digestive Surgery, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D004249:DNA Damage; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077337:Vorinostat; D019061:src-Family Kinases