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.
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Research Article|
September 12 2011
Inhibition of cell growth and up-regulation of MAD2 in human oesophageal squamous cell carcinoma after treatment with the Src/Abl inhibitor dasatinib
Li Wang;
Li Wang
*Thoracic Surgery Center, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China
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Bin Guo;
Bin Guo
†Department of Ophthalmology, No. 81 Hospital, Nanjing 210002, Jiangsu Province, China
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Ruwen Wang;
*Thoracic Surgery Center, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China
Correspondence: Professor Ruwen Wang (e-mail [email protected]).
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Yaoguang Jiang;
Yaoguang Jiang
*Thoracic Surgery Center, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China
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Shukui Qin;
Shukui Qin
‡Tumor Center of PLA, No. 81 Hospital, Nanjing 210002, Jiangsu Province, China
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Shuhui Liang;
Shuhui Liang
§State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China
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Yunping Zhao;
Yunping Zhao
*Thoracic Surgery Center, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China
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Wei Guo;
Wei Guo
*Thoracic Surgery Center, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China
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Kun Li;
Kun Li
*Thoracic Surgery Center, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China
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Xiaoqing Fan
Xiaoqing Fan
*Thoracic Surgery Center, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China
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Publisher: Portland Press Ltd
Received:
May 05 2011
Revision Received:
July 11 2011
Accepted:
July 14 2011
Accepted Manuscript online:
July 14 2011
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2012 Biochemical Society
2012
Clin Sci (Lond) (2012) 122 (1): 13–24.
Article history
Received:
May 05 2011
Revision Received:
July 11 2011
Accepted:
July 14 2011
Accepted Manuscript online:
July 14 2011
Citation
Li Wang, Bin Guo, Ruwen Wang, Yaoguang Jiang, Shukui Qin, Shuhui Liang, Yunping Zhao, Wei Guo, Kun Li, Xiaoqing Fan; Inhibition of cell growth and up-regulation of MAD2 in human oesophageal squamous cell carcinoma after treatment with the Src/Abl inhibitor dasatinib. Clin Sci (Lond) 1 January 2012; 122 (1): 13–24. doi: https://doi.org/10.1042/CS20110230
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