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A framework for the in vitro evaluation of cancer-relevant molecular characteristics and mitogenic potency of insulin analogues
Epidemiological and laboratory studies raise the possibility of a link between clinically prescribed insulin analogues and increased cancer risk. Accordingly, there is a regulatory mandate for cancer-related pre-clinical safety evaluation during insulin analogue development, but currently, there is...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552242/ https://www.ncbi.nlm.nih.gov/pubmed/26026165 http://dx.doi.org/10.1093/carcin/bgv071 |
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author | Baricevic, Ivona Jones, David R. Roberts, Darren L. Lutzen, Anne Lundby, Anders Worm, Jesper Hansen, Bo F. Renehan, Andrew G. |
author_facet | Baricevic, Ivona Jones, David R. Roberts, Darren L. Lutzen, Anne Lundby, Anders Worm, Jesper Hansen, Bo F. Renehan, Andrew G. |
author_sort | Baricevic, Ivona |
collection | PubMed |
description | Epidemiological and laboratory studies raise the possibility of a link between clinically prescribed insulin analogues and increased cancer risk. Accordingly, there is a regulatory mandate for cancer-related pre-clinical safety evaluation during insulin analogue development, but currently, there is no standardized framework for such in vitro evaluation. We tested human insulin; the super-mitogenic insulin, X10 and insulin-like growth factor I, in four cancer cell lines with a range of insulin-like growth factor-I receptor (IGF-IR)/IR (insulin receptor) ratios (HCT 116, HT-29, COLO 205 and MCF7) and related these to IGF-IR and IR expression in 17 human adenocarcinomas. All cell types were IR-A isoform dominant. We determined IGF-IR/IR signalling pathway endpoints in dose- and time-varying experiments, and performed mitogenic dose–response equivalent assays to derive EC(50) values, and correlated these with IGF-IR/IR ratios. We superimposed relative EC(50) values onto data from the literature in a meta-analysis. The IGF-IR/IR ratios varied from <1 to 12 in the selected cell lines; similar pattern ranges were observed in human adenocarcinomas. The three ligands demonstrated differential IR/IGF-IR and Akt phosphorylation, which correlated with cell-specific IGF-IR/IR ratios. Mitogenic profiles of X10 mimicked those for insulin-like growth factor I (IGF-I) and correlated with IGF-IR/IR ratios. The meta-analysis, adding data from five additional studies, supported the hypothesis that ligand mitogenic potency, relative to human insulin, increases with increasing cell-specific IGF-IR/IR ratio. This study established a framework for the in vitro evaluation of cancer-relevant bioassays for comparisons of insulin analogues, and specifically consolidated earlier studies that determination of the cell-specific IGF-IR/IR ratio is crucial for the interpretation of ranking relative biological activities. |
format | Online Article Text |
id | pubmed-4552242 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-45522422015-08-31 A framework for the in vitro evaluation of cancer-relevant molecular characteristics and mitogenic potency of insulin analogues Baricevic, Ivona Jones, David R. Roberts, Darren L. Lutzen, Anne Lundby, Anders Worm, Jesper Hansen, Bo F. Renehan, Andrew G. Carcinogenesis Original Manuscript Epidemiological and laboratory studies raise the possibility of a link between clinically prescribed insulin analogues and increased cancer risk. Accordingly, there is a regulatory mandate for cancer-related pre-clinical safety evaluation during insulin analogue development, but currently, there is no standardized framework for such in vitro evaluation. We tested human insulin; the super-mitogenic insulin, X10 and insulin-like growth factor I, in four cancer cell lines with a range of insulin-like growth factor-I receptor (IGF-IR)/IR (insulin receptor) ratios (HCT 116, HT-29, COLO 205 and MCF7) and related these to IGF-IR and IR expression in 17 human adenocarcinomas. All cell types were IR-A isoform dominant. We determined IGF-IR/IR signalling pathway endpoints in dose- and time-varying experiments, and performed mitogenic dose–response equivalent assays to derive EC(50) values, and correlated these with IGF-IR/IR ratios. We superimposed relative EC(50) values onto data from the literature in a meta-analysis. The IGF-IR/IR ratios varied from <1 to 12 in the selected cell lines; similar pattern ranges were observed in human adenocarcinomas. The three ligands demonstrated differential IR/IGF-IR and Akt phosphorylation, which correlated with cell-specific IGF-IR/IR ratios. Mitogenic profiles of X10 mimicked those for insulin-like growth factor I (IGF-I) and correlated with IGF-IR/IR ratios. The meta-analysis, adding data from five additional studies, supported the hypothesis that ligand mitogenic potency, relative to human insulin, increases with increasing cell-specific IGF-IR/IR ratio. This study established a framework for the in vitro evaluation of cancer-relevant bioassays for comparisons of insulin analogues, and specifically consolidated earlier studies that determination of the cell-specific IGF-IR/IR ratio is crucial for the interpretation of ranking relative biological activities. Oxford University Press 2015-09 2015-05-30 /pmc/articles/PMC4552242/ /pubmed/26026165 http://dx.doi.org/10.1093/carcin/bgv071 Text en © The Author 2015. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Original Manuscript Baricevic, Ivona Jones, David R. Roberts, Darren L. Lutzen, Anne Lundby, Anders Worm, Jesper Hansen, Bo F. Renehan, Andrew G. A framework for the in vitro evaluation of cancer-relevant molecular characteristics and mitogenic potency of insulin analogues |
title | A framework for the in vitro evaluation of cancer-relevant molecular characteristics and mitogenic potency of insulin analogues |
title_full | A framework for the in vitro evaluation of cancer-relevant molecular characteristics and mitogenic potency of insulin analogues |
title_fullStr | A framework for the in vitro evaluation of cancer-relevant molecular characteristics and mitogenic potency of insulin analogues |
title_full_unstemmed | A framework for the in vitro evaluation of cancer-relevant molecular characteristics and mitogenic potency of insulin analogues |
title_short | A framework for the in vitro evaluation of cancer-relevant molecular characteristics and mitogenic potency of insulin analogues |
title_sort | framework for the in vitro evaluation of cancer-relevant molecular characteristics and mitogenic potency of insulin analogues |
topic | Original Manuscript |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552242/ https://www.ncbi.nlm.nih.gov/pubmed/26026165 http://dx.doi.org/10.1093/carcin/bgv071 |
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