Synergistic antitumor effects of dasatinib and oxaliplatin in gastric cancer cells

• Published in: Cancer chemotherapy and pharmacology 2013-07, Vol.72 (1), p.35-44
• Main Authors: Shi, Min, Lou, Bingxiang, Ji, Jun, Shi, Hailong, Zhou, Chenfei, Yu, Yingyan, Liu, Bingya, Zhu, Zhenggang, Zhang, Jun
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Cancer Research; Cell Line; Cell Line, Tumor; Dasatinib; Drug Synergism; Gastric Mucosa - drug effects; Gastric Mucosa - metabolism; Gastric Mucosa - pathology; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Inhibitory Concentration 50; Male; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Nude; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Oncology; Organoplatinum Compounds - administration & dosage; Organoplatinum Compounds - adverse effects; Organoplatinum Compounds - pharmacology; Organoplatinum Compounds - therapeutic use; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Phosphorylation - drug effects; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein Processing, Post-Translational - drug effects; Proto-Oncogene Proteins pp60(c-src) - antagonists & inhibitors; Proto-Oncogene Proteins pp60(c-src) - metabolism; Pyrimidines - administration & dosage; Pyrimidines - adverse effects; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Random Allocation; RNA Interference; Stomach Neoplasms - drug therapy; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Thiazoles - administration & dosage; Thiazoles - adverse effects; Thiazoles - pharmacology; Thiazoles - therapeutic use; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-013-2166-1

Purpose The aim of this study is to investigate whether Dasatinib, a Src inhibitor, has the synergistic effect with oxaliplatin in treating gastric cancer cells. Methods The baseline levels of total Src and p-Src in 10 human gastric cancer cell lines and gastric mucosa epithelial cell line GES-1 were detected by Western blot (WB). The changes of Src and p-Src expression after oxaliplatin exposure were evaluated by WB. The combination indices and clonogenic assay were used to evaluate the synergistic effects of dasatinib with oxaliplatin on cell growth and proliferation in vitro. Gastric cancer xenografts in nude mice were established and treated by oxaliplatin with or without dasatinib. The tumor growth curves were calculated and the impacts of different treatment on the tumor proliferation and src protein expression in gastric cancer xenografts were determined by immunohistochemistry staining and WB. Results The different levels of Src expression in gastric cancer cells were related with their different sensitivity to oxaliplatin. The expression of p-Src, but not total Src, was elevated after oxaliplatin exposure both in vitro and in vivo. Dasatinib could dramatically inhibit p-Src expression, and combination indices demonstrated that dasatinib and oxaliplatin were synergistic in inhibiting gastric cancer cell growth. Dasatinib plus oxaliplatin were more effective in inhibiting clone formation than oxaliplatin or dasatinib monotherapy in clonogenic assay. The tumor volume and tumor weight of xenografts were significantly lower in doublet treatment group than those in single-agent treatment groups. Conclusions Dasatinib plays synergistic role with oxaliplatin in inhibiting gastric cancer cell growth both in vitro and in vivo, via inhibiting Src activity stimulated by oxaliplatin.