Synergistic Activity of the Src Family Kinase Inhibitor Dasatinib and Oxaliplatin in Colon Carcinoma Cells Is Mediated by Oxidative Stress
- 30 April 2009
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 69 (9), 3842-3849
- https://doi.org/10.1158/0008-5472.can-08-2246
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 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. [Cancer Res 2009;69(9):3842–9]Keywords
Other Versions
This publication has 46 references indexed in Scilit:
- Protein cysteine sulfinic acid reductase (sulfiredoxin) as a regulator of cell proliferation and drug responseOncogene, 2008
- Src Continues Aging: Current and Future Clinical DirectionsClinical Cancer Research, 2007
- The resurgence of platinum-based cancer chemotherapyNature Reviews Cancer, 2007
- Vascular endothelial growth factor receptor-1 mediates migration of human colorectal carcinoma cells by activation of Src family kinasesBritish Journal of Cancer, 2006
- Expression of Kinase-defective Mutants of c-Src in Human Metastatic Colon Cancer Cells Decreases Bcl-xL and Increases Oxaliplatin- and Fas-induced ApoptosisPublished by Elsevier BV ,2004
- ROS stress in cancer cells and therapeutic implicationsDrug Resistance Updates, 2004
- Cisplatin-induced activation of the EGF receptorOncogene, 2002
- Src activation regulates anoikis in human colon tumor cell linesOncogene, 2002
- Activation of Src kinase in primary colorectal carcinomaCancer, 2002
- Cisplatin Generates Superoxide Anion by Interaction with DNA in a Cell-Free SystemBiochemical and Biophysical Research Communications, 1994