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Synergistic Activity of the Src Family Kinase Inhibitor Dasatinib and Oxaliplatin in Colon Carcinoma Cells Is Mediated by Oxidative Stress
Open accessPublished version of a preprint
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]
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“Oxaliplatin was proven to activate c-Src through a ROS-dependent mechanism”
From Dasatinib, a Src inhibitor, sensitizes liver metastatic colorectal carcinoma to oxaliplatin in tumors with high levels of phospho-Src (2016) · cites this paper as [48]
In the citing paper
“Combination therapy with dasatinib and oxaliplatin in a CRC metastatic murine model resulted in smaller tumors than therapy with either agent alone.”
From Dasatinib, a Src inhibitor, sensitizes liver metastatic colorectal carcinoma to oxaliplatin in tumors with high levels of phospho-Src (2016) · cites this paper as [48]
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“dasatinib-mediated c-Src inhibition sensitized cells to oxaliplatin activity [48].”
From Dasatinib, a Src inhibitor, sensitizes liver metastatic colorectal carcinoma to oxaliplatin in tumors with high levels of phospho-Src (2016) · cites this paper as [48]
In the citing paper
“Combined treatment with dasatinib and oxaliplatin in a CRC metastatic mouse model presented an outcome of smaller tumors compared to single-agent therapy either way.Oxaliplatin was proved to activate c-src through a ROS-dependent mechanism, thereby, c-src inhibition by dasatinib sensitized cells to oxaliplatin activity.95”
From The molecular rationale of Src inhibition in colorectal carcinomas (2014) · cites this paper as [95]
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Metadata
- Authors
- Kopetz, S., Lesslie, D. P., Dallas, N. A., Park, S. I., Johnson, M., Parikh, N. U., Kim, M. P., Abbruzzese, J. L., Ellis, L. M., Chandra, J., & Gallick, G. E.
- Affiliations
- 1Cancer Biology, Departments of
- 2Gastrointestinal Medical Oncology,
- The University of Texas MD Anderson Cancer Center (US)
- ORCID
- Venue
- Cancer Research
- Published
- 2009-04-30
- Volume
- 69
- Issue
- 9
- Pages
- 3842-3849
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2709758
- OpenAlex
- W2092343827
- Cited by
- 160
- References
- 46
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 9 · 2022: 9 · 2021: 7 · 2020: 7 · 2019: 4 · 2018: 6 · 2017: 7 · 2016: 11 · 2015: 9 · 2014: 8 · 2013: 12 · 2012: 16
- FWCI
- 9.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5p20ca101936-05, KL2TR000370, CA088084, CA101936)
- National Cancer Institute (U54CA090810, K23CA136980, T-32 CA 09599, P20-CA101936, L30 CA124227, T32CA009599, K12CA088084)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Mechanisms and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- dasatinib, oxaliplatin, Src family kinases, colorectal cancer, combination chemotherapy, oxidative stress, reactive oxygen species, drug synergy, chemoresistance, antioxidants, colorectal liver metastases, angiogenesis, cell proliferation
- MeSH terms
- Dasatinib, Oxaliplatin, Animals, Antineoplastic Combined Chemotherapy Protocols, Colonic Neoplasms, Drug Synergism, Humans, Liver Neoplasms, Experimental, Male, Mice, Nude, Neovascularization, Pathologic, Organoplatinum Compounds, Pyrimidines, Random Allocation, Thiazoles, Down-Regulation, Apoptosis, Reactive Oxygen Species, Oxidative Stress, src-Family Kinases, HT29 Cells, Vascular Endothelial Growth Factor A, HCT116 Cells, Protein Kinase Inhibitors, Cell Growth Processes, Mice
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