The DOI matches its Crossref record; 46 of the 46 references it cites were found in a registry or an index.
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]
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
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]
In the citing paper
“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
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Chou, T.-C., & Talalay, P. (1984) · Advances in Enzyme Regulation · doi:10.1016/0065-2571(84)90007-4 · Cited by 7,178
Chou, T.-C. (2006) · Pharmacological Reviews · doi:10.1124/pr.58.3.10 · Cited by 5,163
The resurgence of platinum-based cancer chemotherapy
Kèlland, L. R. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2167 · Cited by 4,733
LeBel, C. P., Ischiropoulos, H., & Bondy, S. C. (1992) · Chemical Research in Toxicology · doi:10.1021/tx00026a012 · Cited by 2,694
ROS stress in cancer cells and therapeutic implications
Pelicano, H., Carney, D. A., & Huang, P. (2004) · Drug Resistance Updates · doi:10.1016/j.drup.2004.01.004 · Cited by 2,031
Lombardo, L. J., Lee, F. Y., Chen, P., Norris, D. J., Barrish, J. C., Behnia, K., Castaneda, S., Cornelius, L. A. M., Das, J., Doweyko, A. M., et al. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm049486a · Cited by 1,303
Angiostatin induces and sustains dormancy of human primary tumors in mice
O’Reilly, M. S., Holmgren, L., Chen, C., & Folkman, J. (1996) · Nature Medicine · doi:10.1038/nm0696-689 · Cited by 1,170
Godwin, A. K., Meister, A., O'Dwyer, P. J., Huang, C. S., Hamilton, T. C., & Anderson, M. E. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.7.3070 · Cited by 926
Yang, A. D., Fan, F., Camp, E. R., Buren, G. V., Liu, W., Somcio, R., Gray, M. J., Cheng, H. Y., Hoff, P. M., & Ellis, L. M. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-0038 · Cited by 526
Self-citationControlling Tumor Growth by Modulating Endogenous Production of Reactive Oxygen Species
Laurent, A., Nicco, C., Chéreau, C., Goulvestre, C., Alexandre, J., Alvès, A., Lévy, E., Goldwasser, F., Panis, Y. H., Soubrane, O., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.948.65.3 · Cited by 516
Giannoni, E., Buricchi, F., Raugei, G., Ramponi, G., & Chiarugi, P. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.15.6391-6403.2005 · Cited by 464
Increase in activity and level of pp60c-src in progressive stages of human colorectal cancer.
Talamonti, M. S., Roh, M. S., Curley, S. A., & Gallick, G. E. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116200 · Cited by 399
Self-citationGray, M. J., Zhang, J., Ellis, L. M., Semenza, G. L., Evans, D. B., Watowich, S. S., & Gallick, G. E. (2005) · Oncogene · doi:10.1038/sj.onc.1208513 · Cited by 378
Self-citationChinery, R., Brockman, J. A., Peeler, M. O., Shyr, Y., Beauchamp, R. D., & Coffey, R. J. (1997) · Nature Medicine · doi:10.1038/nm1197-1233 · Cited by 334
Takahashi, Y. (1997) · Archives of Surgery · doi:10.1001/archsurg.1997.01430290087018 · Cited by 329
Kruidering, M., van de Water, B., de Heer, E., Mulder, G. J., & Nagelkerke, J. F. (1997) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)36493-6 · Cited by 325
EphrinB Phosphorylation and Reverse Signaling
Palmer, A., Zimmer, M., Erdmann, K. S., Eulenburg, V., Porthin, A., Heumann, R., Deutsch, U., & Klein, R. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00488-4 · Cited by 305
New Roles for Src Kinases in Control of Cell Survival and Angiogenesis
Schlessinger, J. (2000) · Cell · doi:10.1016/s0092-8674(00)80664-9 · Cited by 302
Cisplatin Generates Superoxide Anion by Interaction with DNA in a Cell-Free System
Masuda, H., Tanaka, T., & Takahama, U. (1994) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1994.2306 · Cited by 254
Activation of Src kinase in primary colorectal carcinoma: An indicator of poor clinical prognosis
Allgayer, H., Boyd, D. D., Heiss, M. M., Abdalla, E. K., Curley, S. A., & Gallick, G. E. (2002) · Cancer · doi:10.1002/cncr.10221 · Cited by 251
Self-citationWitte, A.-B., Anestål, K., Jerremalm, E., Ehrsson, H., & Arnér, E. S. J. (2005) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2005.04.025 · Cited by 225
Treatment for Advanced Tumors: Src Reclaims Center Stage
Summy, J. M., & Gallick, G. E. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-2692 · Cited by 224
Self-citationSrc activation regulates anoikis in human colon tumor cell lines
Windham, T. C., Parikh, N. U., Siwak, D. R., Summy, J. M., McConkey, D. J., Kraker, A. J., & Gallick, G. E. (2002) · Oncogene · doi:10.1038/sj.onc.1205989 · Cited by 219
Self-citationEllis, L. M., Staley, C. A., Liu, W., Fleming, R., Parikh, N. U., Bucana, C. D., & Gallick, G. E. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.2.1052 · Cited by 200
Self-citationAlexandre, J., Nicco, C., Chéreau, C., Laurent, A., Weill, B. J., Goldwasser, F., & Batteux, F. (2006) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djj049 · Cited by 200
Sasada, T., Iwata, S., Sato, N., Kitaoka, Y., Hirota, K., Nakamura, K., Nishiyama, A., Taniguchi, Y., Takabayashi, A., & Yodoi, J. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118668 · Cited by 199
Duxbury, M. S., Ito, H., Zinner, M. J., Ashley, S. W., & Whang, E. E. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-1183-3 · Cited by 192
Reinmuth, N., Fan, F., Liu, W., Parikh, A. A., Stoeltzing, O., Jung, Y. D., Bucana, C. D., Radinsky, R., Gallick, G. E., & Ellis, L. M. (2002) · Laboratory Investigation · doi:10.1097/01.lab.0000032411.41603.c2 · Cited by 174
Self-citationMiyajima, A., Nakashima, J., Yoshioka, K., Tachibana, M., Tazaki, H., & Murai, M. (1997) · British Journal of Cancer · doi:10.1038/bjc.1997.363 · Cited by 171
Lu, Y., Li, X., Liang, K., Luwor, R., Siddik, Z. H., Mills, G. B., Mendelsohn, J., & Fan, Z. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0589 · Cited by 170
Therapeutic Targeting of Neuropilin-2 on Colorectal Carcinoma Cells Implanted in the Murine Liver
Gray, M. J., Buren, G. V., Dallas, N. A., Xia, L., Wang, L., Yang, A. D., Somcio, R., Lin, Y. G., Lim, S. W., Fan, F., et al. (2008) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djm279 · Cited by 162
Self-citationCisplatin-induced activation of the EGF receptor
Benhar, M., Engelberg, D., & Levitzki, A. (2002) · Oncogene · doi:10.1038/sj.onc.1205980 · Cited by 146
Lesslie, D. P., Summy, J. M., Parikh, N. U., Fan, F., Trevino, J., Sawyer, T. K., Metcalf, C. A., Shakespeare, W. C., Hicklin, D. J., Ellis, L. M., et al. (2006) · British Journal of Cancer · doi:10.1038/sj.bjc.6603143 · Cited by 126
Self-citationSrc continues aging: current and future clinical directions
Kopetz, S., Shah, A. N., & Gallick, G. E. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-1902 · Cited by 111
Self-citationSite-Specific Differences in pp60c-src Activity in Human Colorectal Metastases
Termuhlen, P. M., Curley, S. A., Talamonti, M. S., Saboorian, M. H., & Gallick, G. E. (1993) · Journal of Surgical Research · doi:10.1006/jsre.1993.1046 · Cited by 108
Self-citationPengetnze, Y., Steed, M., Roby, K. F., Terranova, P. F., & Taylor, C. C. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2003.08.012 · Cited by 107
Trevino, J. G., Summy, J. M., Gray, M. J., Nilsson, M. B., Lesslie, D. P., Baker, C. H., & Gallick, G. E. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-3858 · Cited by 83
Self-citationGourdier, I., Crabbé, L., Andréau, K., Pau, B., & Kroemer, G. (2004) · Oncogene · doi:10.1038/sj.onc.1208047 · Cited by 82
George, J. A., Chen, T., & Taylor, C. C. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-1822 · Cited by 78
Pu, M., Akhand, A. A., Kato, M., Hamaguchi, M., Koike, T., Iwata, H., Sabe, H., Suzuki, H., & Nakashima, I. (1996) · PubMed · Cited by 66
(1996) · PubMed · Cited by 63
Self-citationLei, K., Townsend, D. M., & Tew, K. D. (2008) · Oncogene · doi:10.1038/onc.2008.132 · Cited by 63
Griffiths, G. J., Koh, M. Y., Brunton, V. G., Cawthorne, C., Reeves, N. A., Greaves, M., Tilby, M. J., Pearson, D. G., Ottley, C. J., Workman, P., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408550200 · Cited by 60
Smith, A. D., Morris, V. C., & Levander, O. A. (2001) · International Journal for Vitamin and Nutrition Research · doi:10.1024/0300-9831.71.1.87 · Cited by 43
N-acetyl-l-cysteine fosters inactivation and transfer to endolysosomes of c-Src
Krasnowska, E. K., Pittaluga, E., Brunati, A. M., Brunelli, R., Costa, G., Spirito, M. D., Serafino, A., Ursini, F., & Parasassi, T. (2008) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2008.09.012 · Cited by 36
Singh, R. A. K., & Sodhi, A. (1998) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/s0167-4889(98)00106-2 · Cited by 17
Research works printed but not linked: 2
- Eng C, Kopetz S, Morris J, et al. Phase II study of the novel oral Src-kinase inhibitor, AZD0530, in previously treated advanced colorectal cancer patients. Proceedings of the 98th Annual Meeting of the AACR; 2008. San Diego, CA. p. LB-76.
- Kopetz S, Wolff RA, C E, et al. Phase IB study of Src inhibition with dasatinib in combination with 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX) and cetuximab in metastatic colorectal cancer. Proceedings of the 98th Annual Meeting of the AACR; 2008 Apr 12-16; San Diego, CA. p. LB-69.
Cited by
Sorted by citations
Gupta, S. C., Hevia, D., Patchva, S., Park, B., Koh, W., & Aggarwal, B. B. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4414 · Cited by 759
Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases
Frentzas, S., Simoneau, È., Bridgeman, V. L., Vermeulen, P., Foo, S., Kostaras, E., Nathan, M. R., Wotherspoon, A. C., Gao, Z., Shi, Y., et al. (2016) · Nature Medicine · doi:10.1038/nm.4197 · Cited by 456
Oxaliplatin elicits mechanical and cold allodynia in rodents via TRPA1 receptor stimulation
Nassini, R., Gees, M., Harrison, S., Siena, G. D., Materazzi, S., Moretto, N., Failli, P., Preti, D., Marchetti, N., Cavazzini, A., et al. (2011) · Pain · doi:10.1016/j.pain.2011.02.051 · Cited by 326
Mao, M., Tian, F., Mariadason, J. M., Tsao, C. C., Lemos, R., Dayyani, F., Gopal, Y. N. V., Jiang, Z.-Q., Wistuba, I. I., Tang, X. M., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-1446 · Cited by 290
Self-citationDasatinib: A potent SRC inhibitor in clinical development for the treatment of solid tumors
Araujo, J., & Logothetis, C. (2010) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2010.02.015 · Cited by 244
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
