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

Abstract

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 ROSdependent 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. [Cancer Res 2009;69(9):3842-9]

Antitumor Activity of Saracatinib (AZD0530), a c-Src/Abl Kinase Inhibitor, Alone or in Combination with Chemotherapeutic Agents in Gastric Cancer

“…One study found that Src activity mediates oxaliplatin (platinum-based chemotherapeutic agent) sensitivity and resistance, and reduced expression of Src leads to increased cytotoxicity in response to oxaliplatin (40). Therefore, sensitivity to cisplatin and other platinum-based chemotherapeutic agents might also be affected by altered Src expression or activity in a similar manner.…”

A bioinformatical and functional approach to identify novel strategies for chemoprevention of colorectal cancer

“…Dasatinib is well tolerated and the drug has entered the clinic for patients with leukemia (Kantarjian et al, 2007). Dasatinib has shown activity against colon cancer cells in preclinical models (Serrels et al, 2006;Kopetz et al, 2009). The potential of dasatinib in adenomas has not been investigated yet.…”

Mucinous ovarian cancer: A therapeutic review

“…Src kinase is a non-receptor tyrosine kinase which is a convergence point for numerous oncogenic pathways [133] and has been implicated in mechanisms of oxaliplatin resistance in colorectal cancer [134]. In preclinical mEOC models, encouraging results have been achieved by targeting Src signaling with dasatinib [135] and KX-01; a novel Src inhibitor and antitubule agent, in synergy with oxaliplatin [136].…”