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Role of Reactive Oxygen Species in the Abrogation of Oxaliplatin Activity by Cetuximab in Colorectal Cancer.
Santoro, Valeria; Jia, Ruochen; Thompson, Hannah; Nijhuis, Anke; Jeffery, Rosemary; Kiakos, Konstantinos; Silver, Andrew R; Hartley, John A; Hochhauser, Daniel.
Afiliación
  • Santoro V; Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, University College London, London, UK (VS, RJ, KK, JAH, DH); Colorectal Cancer Genetics Group, Blizard Institute, London, UK (HT, AN, RJ, ARS);
  • Jia R; Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, University College London, London, UK (VS, RJ, KK, JAH, DH); Colorectal Cancer Genetics Group, Blizard Institute, London, UK (HT, AN, RJ, ARS);
  • Thompson H; Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, University College London, London, UK (VS, RJ, KK, JAH, DH); Colorectal Cancer Genetics Group, Blizard Institute, London, UK (HT, AN, RJ, ARS);
  • Nijhuis A; Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, University College London, London, UK (VS, RJ, KK, JAH, DH); Colorectal Cancer Genetics Group, Blizard Institute, London, UK (HT, AN, RJ, ARS);
  • Jeffery R; Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, University College London, London, UK (VS, RJ, KK, JAH, DH); Colorectal Cancer Genetics Group, Blizard Institute, London, UK (HT, AN, RJ, ARS);
  • Kiakos K; Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, University College London, London, UK (VS, RJ, KK, JAH, DH); Colorectal Cancer Genetics Group, Blizard Institute, London, UK (HT, AN, RJ, ARS);
  • Silver AR; Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, University College London, London, UK (VS, RJ, KK, JAH, DH); Colorectal Cancer Genetics Group, Blizard Institute, London, UK (HT, AN, RJ, ARS);
  • Hartley JA; Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, University College London, London, UK (VS, RJ, KK, JAH, DH); Colorectal Cancer Genetics Group, Blizard Institute, London, UK (HT, AN, RJ, ARS);
  • Hochhauser D; Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, University College London, London, UK (VS, RJ, KK, JAH, DH); Colorectal Cancer Genetics Group, Blizard Institute, London, UK (HT, AN, RJ, ARS); d.hochhauser@ucl.ac.uk.
J Natl Cancer Inst ; 108(6): djv394, 2016 Jun.
Article en En | MEDLINE | ID: mdl-26719345
ABSTRACT

BACKGROUND:

The antibody cetuximab, targeting epidermal growth factor receptor (EGFR), is used to treat metastatic colorectal cancer (mCRC). Clinical trials suggest reduced benefit from the combination of cetuximab with oxaliplatin. The aim of this study was to investigate potential negative interactions between cetuximab and oxaliplatin.

METHODS:

Thiazolyl blue tetrazolium bromide (MTT) assay and Calcusyn software were used to characterize drug interactions. Reactive oxygen species (ROS) were measured by flow cytometry and real-time polymerase chain reaction oxidative stress arrays identified genes regulating ROS production. Chromatin immunoprecipitation (ChIP) measured signal transducer and activator of transcription 1 (STAT-1) binding to dual oxidase 2 (DUOX2) promoter. SW48, DLD-1 KRAS wild-type cell lines and DLD-1 xenograft models exposed to cetuximab, oxaliplatin, or oxaliplatin + cetuximab (control [saline]; n = 3 mice per treatment group) were used. Statistical tests were two-sided.

RESULTS:

Cetuximab and oxaliplatin exhibited antagonistic effects on cellular proliferation and apoptosis (caspase 3/7 activity reduced by 1.4-fold, 95% confidence interval [CI] = 0.78 to 2.11, P = .003) as opposed to synergistic effects observed with the irinotecan metabolite 7-Ethyl-10-hydroxycamptothecin (SN-38). Although both oxaliplatin and SN-38 produced ROS, only oxaliplatin-mediated apoptosis was ROS dependent. Production of ROS by oxaliplatin was secondary to STAT1-mediated transcriptional upregulation of DUOX2 (3.1-fold, 95% CI = 1.75 to 2.41, P < .001). Inhibition of DUOX2 induction and p38 activation by cetuximab reduced oxaliplatin cytotoxicity.

CONCLUSIONS:

Inhibition of STAT1 and DUOX2-mediated ROS generation by cetuximab impairs p38-dependent apoptosis by oxaliplatin in preclinical models and may contribute to reduced efficacy in clinical settings. Understanding the rationale for unexpected trial results will inform improved rationales for combining EGFR inhibitors with chemotherapeutic agents in future therapeutic use.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Compuestos Organoplatinos / Neoplasias Colorrectales / Protocolos de Quimioterapia Combinada Antineoplásica / Especies Reactivas de Oxígeno / Receptores ErbB / Cetuximab Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Natl Cancer Inst Año: 2016 Tipo del documento: Article
Texto completo
Añadir a Mi BVS
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Compuestos Organoplatinos / Neoplasias Colorrectales / Protocolos de Quimioterapia Combinada Antineoplásica / Especies Reactivas de Oxígeno / Receptores ErbB / Cetuximab Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Natl Cancer Inst Año: 2016 Tipo del documento: Article