A framework for the in vitro evaluation of cancer-relevant molecular characteristics and mitogenic potency of insulin analogues.
Jones, David R
Roberts, Darren L
Renehan, Andrew G
AffiliationInstitute of Cancer Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
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AbstractEpidemiological and laboratory studies raised 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 standardised framework for such in vitro evaluation. We tested human insulin; the super-mitogenic insulin, X10; and IGF-I, in four cancer cell lines with a range of IGF-IR/IR ratios (HCT 116, HT-29, COLO 205, MCF7), and related these to IGF-IR and IR expression in 17 human adenocarcinomas. All cell types were IRA 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 EC50 values, and correlated these with IGF-IR/IR ratios. We superimposed relative EC50 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 IGF-I, and correlated with IGF-IR/IR ratios. The meta-analysis, adding data from 5 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 bio-assays 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.
CitationA framework for the in vitro evaluation of cancer-relevant molecular characteristics and mitogenic potency of insulin analogues. 2015: Carcinogenesis
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- Differential insulin-like growth factor I receptor signaling and function in estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cells.
- Authors: Bartucci M, Morelli C, Mauro L, Andò S, Surmacz E
- Issue date: 2001 Sep 15
- Analysis of signaling pathways related to cell proliferation stimulated by insulin analogs in human mammary epithelial cell lines.
- Authors: Shukla A, Grisouard J, Ehemann V, Hermani A, Enzmann H, Mayer D
- Issue date: 2009 Jun
- Classifying the adverse mitogenic mode of action of insulin analogues using a novel mechanism-based genetically engineered human breast cancer cell panel.
- Authors: ter Braak B, Siezen CL, Kannegieter N, Koedoot E, van de Water B, van der Laan JW
- Issue date: 2014 Apr
- In IGF-I receptor-deficient leiomyosarcoma cells autocrine IGF-II induces cell invasion and protection from apoptosis via the insulin receptor isoform A.
- Authors: Sciacca L, Mineo R, Pandini G, Murabito A, Vigneri R, Belfiore A
- Issue date: 2002 Nov 28