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Different responses of colorectal cancer cells to alternative sequences of cetuximab and oxaliplatin

Therapeutic protocols including EGFR antibodies in the context of oxaliplatin-based regimens have variable clinical effect in colorectal cancer. Here, we tested the effect of the EGFR antibody cetuximab in different sequential combinations with oxaliplatin on the growth of colorectal cancer cells in...

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Autores principales: Narvi, Elli, Vaparanta, Katri, Karrila, Anna, Chakroborty, Deepankar, Knuutila, Sakari, Pulliainen, Arto, Sundvall, Maria, Elenius, Klaus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224565/
https://www.ncbi.nlm.nih.gov/pubmed/30410004
http://dx.doi.org/10.1038/s41598-018-34938-y
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author Narvi, Elli
Vaparanta, Katri
Karrila, Anna
Chakroborty, Deepankar
Knuutila, Sakari
Pulliainen, Arto
Sundvall, Maria
Elenius, Klaus
author_facet Narvi, Elli
Vaparanta, Katri
Karrila, Anna
Chakroborty, Deepankar
Knuutila, Sakari
Pulliainen, Arto
Sundvall, Maria
Elenius, Klaus
author_sort Narvi, Elli
collection PubMed
description Therapeutic protocols including EGFR antibodies in the context of oxaliplatin-based regimens have variable clinical effect in colorectal cancer. Here, we tested the effect of the EGFR antibody cetuximab in different sequential combinations with oxaliplatin on the growth of colorectal cancer cells in vitro and in vivo. Cetuximab reduced the efficacy of oxaliplatin when administered before oxaliplatin but provided additive effect when administered after oxaliplatin regardless of the KRAS or BRAF mutation status of the cells. Systemic gene expression and protein phosphorylation screens revealed alternatively activated pathways regulating apoptosis, cell cycle and DNA damage response. Functional assays indicated that cetuximab-induced arrest of the cells into the G1 phase of the cell cycle was associated with reduced responsiveness of the cells to subsequent treatment with oxaliplatin. In contrast, oxaliplatin-enhanced responsiveness to subsequent treatment with cetuximab was associated with increased apoptosis, inhibition of STAT3 activity and increased EGFR down-regulation. This preclinical study indicates that optimizing the sequence of administration may enhance the antitumor effect of combination therapy with EGFR antibodies and oxaliplatin.
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spelling pubmed-62245652018-11-13 Different responses of colorectal cancer cells to alternative sequences of cetuximab and oxaliplatin Narvi, Elli Vaparanta, Katri Karrila, Anna Chakroborty, Deepankar Knuutila, Sakari Pulliainen, Arto Sundvall, Maria Elenius, Klaus Sci Rep Article Therapeutic protocols including EGFR antibodies in the context of oxaliplatin-based regimens have variable clinical effect in colorectal cancer. Here, we tested the effect of the EGFR antibody cetuximab in different sequential combinations with oxaliplatin on the growth of colorectal cancer cells in vitro and in vivo. Cetuximab reduced the efficacy of oxaliplatin when administered before oxaliplatin but provided additive effect when administered after oxaliplatin regardless of the KRAS or BRAF mutation status of the cells. Systemic gene expression and protein phosphorylation screens revealed alternatively activated pathways regulating apoptosis, cell cycle and DNA damage response. Functional assays indicated that cetuximab-induced arrest of the cells into the G1 phase of the cell cycle was associated with reduced responsiveness of the cells to subsequent treatment with oxaliplatin. In contrast, oxaliplatin-enhanced responsiveness to subsequent treatment with cetuximab was associated with increased apoptosis, inhibition of STAT3 activity and increased EGFR down-regulation. This preclinical study indicates that optimizing the sequence of administration may enhance the antitumor effect of combination therapy with EGFR antibodies and oxaliplatin. Nature Publishing Group UK 2018-11-08 /pmc/articles/PMC6224565/ /pubmed/30410004 http://dx.doi.org/10.1038/s41598-018-34938-y Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Narvi, Elli
Vaparanta, Katri
Karrila, Anna
Chakroborty, Deepankar
Knuutila, Sakari
Pulliainen, Arto
Sundvall, Maria
Elenius, Klaus
Different responses of colorectal cancer cells to alternative sequences of cetuximab and oxaliplatin
title Different responses of colorectal cancer cells to alternative sequences of cetuximab and oxaliplatin
title_full Different responses of colorectal cancer cells to alternative sequences of cetuximab and oxaliplatin
title_fullStr Different responses of colorectal cancer cells to alternative sequences of cetuximab and oxaliplatin
title_full_unstemmed Different responses of colorectal cancer cells to alternative sequences of cetuximab and oxaliplatin
title_short Different responses of colorectal cancer cells to alternative sequences of cetuximab and oxaliplatin
title_sort different responses of colorectal cancer cells to alternative sequences of cetuximab and oxaliplatin
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224565/
https://www.ncbi.nlm.nih.gov/pubmed/30410004
http://dx.doi.org/10.1038/s41598-018-34938-y
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