Inhibition of cell growth and up-regulation of MAD2 in human oesophageal squamous cell carcinoma after treatment with the Src/Abl inhibitor dasatinib

• Published in: Clinical science (1979) Vol. 122; no. 1-2; pp. 13 - 24
• Main Authors: Wang, Li, Guo, Bin, Wang, Ruwen, Jiang, Yaoguang, Qin, Shukui, Liang, Shuhui, Zhao, Yunping, Guo, Wei, Li, Kun, Fan, Xiaoqing
• Format: Journal Article
• Language: English
• Published: London Portland Press 2012
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Calcium-Binding Proteins - metabolism; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Cycle - drug effects; Cell Cycle Proteins - metabolism; Cell Line; Cell Line, Tumor; Cell Proliferation - drug effects; Chromosome aberrations; Dasatinib; Drug Synergism; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Esophagus; Female; Gastroenterology. Liver. Pancreas. Abdomen; General aspects; Humans; Mad2 Proteins; Medical genetics; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-abl - antagonists & inhibitors; Proto-Oncogene Proteins c-abl - metabolism; Pyrimidines - pharmacology; Repressor Proteins - metabolism; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - metabolism; Taxoids - pharmacology; Thiazoles - pharmacology; Tumors; Up-Regulation - drug effects; Xenograft Model Antitumor Assays; Chromosomal aberration; Antineoplastic agent; Cell proliferation; Carceral environment; Arrest; Mitosis; Src; Non-specific serine/threonine protein kinase; Esophageal disease; Esophagus squamous cell carcinoma; Bcr/Abl; Esophagus cancer; Abnormal chromosome C9; Regulation(control); mitotic arrest-deficient 2 (MAD2); Taxane derivatives; Abnormal chromosome G22; Inhibition; Antimitotic; Protein-tyrosine kinase; Hybrid gene; Protooncogene; Chromosome translocation; Human; Dasatinib; Enzyme; Tyrosine kinase inhibitor; Transferases; Docetaxel; Malignant tumor; Philadelphia chromosome; Treatment; bcr gene; oesophageal squamous cell carcinoma; C-Onc gene; Abnormal chromosome; Digestive diseases; Multikinase inhibitor; Cancer
• ISSN: 0143-5221; 1470-8736
• DOI: 10.1042/CS20110230

Aberrant expression and/or activity of the non-receptor protein tyrosine kinase SFK (Src family kinase) members are commonly observed in progressive stages of human tumours. The aim of the present study was to investigate whether Src is a potential drug target for treating oesophageal squamous cell carcinoma. Compared with the human immortalized oesophageal epithelial cell line SHEE, oesophageal squamous cell carcinoma cells have increased tyrosine phosphorylation activities. We have explored the therapeutic potential of dasatinib, a small-molecule inhibitor that targets multiple cytosolic and membrane-bound tyrosine kinases, for the treatment of oesophageal squamous cell carcinoma. We examined that the effects of dasatinib on proliferation, invasion, apoptosis, spindle checkpoint, cell-cycle arrest and kinase activity in vitro using three human oesophageal carcinoma cell lines KYSE30, KYSE180 and EC109. In nude mouse models, dasatinib treatment effectively inhibited the expression of activated Src, resulting in the inhibition of tumour growth. Multiple drug effect isobologram analysis was used to study interactions with the chemotherapeutic drug docetaxel. As expected, the three oesophageal carcinoma cell lines were highly sensitive to dasatinib, but SHEE cells were not sensitive to this drug. Concentration-dependent anti-proliferative effects of dasatinib were observed in the three oesophageal carcinoma cell lines. Dasatinib significantly inhibited oesophageal carcinoma cell invasion and up-regulation of MAD2 (mitotic arrest-deficient 2), as well as inducing cell apoptosis and cell-cycle arrest. Additive and synergistic interactions were observed for the combination of dasatinib and docetaxel. Therefore it was concluded that dasatinib blocks the G₁/S transition and inhibits cell growth. These results provided a clear biological rationale to test dasatinib as a single agent or in combination with chemotherapy in oesophageal squamous cell carcinoma. Moreover, we have shown in vitro and in vivo that dasatinib might have therapeutic benefit for patients with oesophageal squamous cell carcinoma who are not eligible for surgery.