Synergistic Activity of the Src Family Kinase Inhibitor Dasatinib and Oxaliplatin in Colon Carcinoma Cells Is Mediated by Oxidative Stress

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 9; pp. 3842 - 3849
• Main Authors: KOPETZ, Scott, LESSLIE, Donald P, GALLICK, Gary E, DALLAS, Nikolas A, PARK, Serk I, JOHNSON, Marjorie, PARIKH, Nila U, KIM, Michael P, ABBRUZZESE, James L, ELLIS, Lee M, CHANDRA, Joya
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.05.2009
• Subjects: Animals; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Cell Growth Processes - drug effects; Colonic Neoplasms - blood supply; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Dasatinib; Down-Regulation; Drug Synergism; Gastroenterology. Liver. Pancreas. Abdomen; HCT116 Cells; HT29 Cells; Humans; Liver Neoplasms, Experimental - drug therapy; Liver Neoplasms, Experimental - metabolism; Male; Medical sciences; Mice; Mice, Nude; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - pathology; Organoplatinum Compounds - administration & dosage; Organoplatinum Compounds - pharmacology; Oxidative Stress - drug effects; Pharmacology. Drug treatments; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Pyrimidines - administration & dosage; Pyrimidines - pharmacology; Random Allocation; Reactive Oxygen Species - metabolism; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - metabolism; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Thiazoles - administration & dosage; Thiazoles - pharmacology; Tumors; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Antineoplastic agent; Dasatinib; Oxidative stress; Tyrosine kinase inhibitor; Malignant tumor; In vitro; Biological activity; Colonic disease; Alkylating agent; Colon cancer; Oxaliplatin; Digestive diseases; Intestinal disease; Multikinase inhibitor; Colon carcinoma; Cell; Cancer; Platinum II Complexes
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-2246

Chemotherapeutic regimens for the treatment of colorectal cancer generally include oxaliplatin, although inherent and acquired resistance is common. One potential mediator of oxaliplatin sensitivity is the nonreceptor protein tyrosine kinase, Src, the activity of which correlates with disease stage and patient survival. Therefore, we investigated the effects of Src inhibition using the tyrosine kinase inhibitor dasatinib on oxaliplatin sensitivity. We show that oxaliplatin acutely activates Src and that combination treatment with dasatinib is synergistic in a cell-line dependent manner, with the level of Src activation correlating with extent of synergy in a panel of six cell lines. Intracellular reactive oxygen species (ROS) are generated after oxaliplatin treatment, and ROS potently activates Src. Pretreatment with antioxidants inhibits oxaliplatin-induced Src activation. In oxaliplatin-resistant cell lines, Src activity is constitutively increased. In a mouse model of colorectal liver metastases, treatment with oxaliplatin also results in chronic Src activation. The combination of dasatinib and oxaliplatin results in significantly smaller tumors compared with single-agent treatment, corresponding with reduced proliferation and angiogenesis. Therefore, we conclude that oxaliplatin activates Src through a ROS-dependent mechanism. Src inhibition increases oxaliplatin activity both in vitro and in vivo. These results suggest that Src inhibitors combined with oxaliplatin may have efficacy in metastatic colon cancer and may provide the first indication of a molecular phenotype that might be susceptible to such combinations.