Synergistic activity of the Src family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress

Scott Kopetz, Donald P. Lesslie, Nikolas A. Dallas, Serkin Park, Marjorie Johnson, Nila U. Parikh, Michael P. Kim, James L. Abbruzzese, Lee M. Ellis, Joya Chandra, Gary E. Gallick

Research output: Contribution to journalArticle

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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. 3842-9

Original languageEnglish
Pages (from-to)3842-3849
Number of pages8
JournalCancer Research
Volume69
Issue number9
DOIs
Publication statusPublished - 2009 May 1
Externally publishedYes

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oxaliplatin
src-Family Kinases
Colon
Oxidative Stress
Carcinoma
Reactive Oxygen Species
Cell Line
Dasatinib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Synergistic activity of the Src family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress. / Kopetz, Scott; Lesslie, Donald P.; Dallas, Nikolas A.; Park, Serkin; Johnson, Marjorie; Parikh, Nila U.; Kim, Michael P.; Abbruzzese, James L.; Ellis, Lee M.; Chandra, Joya; Gallick, Gary E.

In: Cancer Research, Vol. 69, No. 9, 01.05.2009, p. 3842-3849.

Research output: Contribution to journalArticle

Kopetz, S, Lesslie, DP, Dallas, NA, Park, S, Johnson, M, Parikh, NU, Kim, MP, Abbruzzese, JL, Ellis, LM, Chandra, J & Gallick, GE 2009, 'Synergistic activity of the Src family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress', Cancer Research, vol. 69, no. 9, pp. 3842-3849. https://doi.org/10.1158/0008-5472.CAN-08-2246
Kopetz, Scott ; Lesslie, Donald P. ; Dallas, Nikolas A. ; Park, Serkin ; Johnson, Marjorie ; Parikh, Nila U. ; Kim, Michael P. ; Abbruzzese, James L. ; Ellis, Lee M. ; Chandra, Joya ; Gallick, Gary E. / Synergistic activity of the Src family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress. In: Cancer Research. 2009 ; Vol. 69, No. 9. pp. 3842-3849.
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AU - Kim, Michael P.

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