Article

Treatment with Insulin Analog X10 and IGF-1 Increases Growth of Colon Cancer Allografts.

Diabetes Research Unit, Novo Nordisk A/S, Maaloev, Denmark.
PLoS ONE (Impact Factor: 3.53). 11/2013; 8(11):e79710. DOI: 10.1371/journal.pone.0079710
Source: PubMed

ABSTRACT Obesity and type 2 diabetes are associated with an increased risk for development of certain forms of cancer, including colon cancer. The publication of highly controversial epidemiological studies in 2009 raised the possibility that use of the insulin analog glargine increases this risk further. However, it is not clear how mitogenic effects of insulin and insulin analogs measured in vitro correlate with tumor growth-promoting effects in vivo. The aim of this study was to examine possible growth-promoting effects of native human insulin, insulin X10 and IGF-1, which are considered positive controls in vitro, in a short-term animal model of an obesity- and diabetes-relevant cancer. We characterized insulin and IGF-1 receptor expression and the response to treatment with insulin, X10 and IGF-1 in the murine colon cancer cell line (MC38 cells) in vitro and in vivo. Furthermore, we examined pharmacokinetics and pharmacodynamics and monitored growth of MC38 cell allografts in mice with diet-induced obesity treated with human insulin, X10 and IGF-1. Treatment with X10 and IGF-1 significantly increased growth of MC38 cell allografts in mice with diet-induced obesity and we can therefore conclude that supra-pharmacological doses of the insulin analog X10, which is super-mitogenic in vitro and increased the incidence of mammary tumors in female rats in a 12-month toxicity study, also increase growth of tumor allografts in a short-term animal model.

0 Bookmarks
 · 
46 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Metabolic syndrome is a cluster of risk factors including obesity, dyslipidemia, hypertension, and insulin resistance. A number of theories have been speculated for the pathogenesis of metabolic syndrome including impaired glucose and lipid metabolism, lipotoxicity, oxidative stress, interrupted neurohormonal regulation and compromised intracellular Ca(2+) handling. Recent evidence has revealed that adults with severe growth hormone (GH) and insulin-like growth factor I (IGF-1) deficiency such as Laron syndrome display increased risk of stroke and cardiovascular diseases. IGF-1 signaling may regulate contractility, metabolism, hypertrophy, apoptosis, autophagy, stem cell regeneration and senescence in the heart to maintain cardiac homeostasis. An inverse relationship between plasma IGF-1 levels and prevalence of metabolic syndrome as well as associated cardiovascular complications has been identified, suggesting the clinical promises of IGF-1 analogues or IGF-1 receptor activation in the management of metabolic and cardiovascular diseases. However, the underlying pathophysiological mechanisms between IGF-1 and metabolic syndrome are still poorly understood. This mini-review will discuss the role of IGF-1 signaling cascade in the prevalence of metabolic syndrome in particular the susceptibility to overnutrition and sedentary life style-induced obesity, dyslipidemia, insulin resistance and other features of metabolic syndrome. Special attention will be dedicated in IGF-1-associated changes in cardiac responses in various metabolic syndrome components such as insulin resistance, obesity, hypertension and dyslipidemia. The potential risk of IGF-1 and IGF-1R stimulation such as tumorigenesis is discussed. Therapeutic promises of IGF-1 and IGF-1 analogues including mecasermin, mecasermin rinfabate and PEGylated IGF-1 will be discussed. Copyright © 2014. Published by Elsevier Inc.
    Biochemical Pharmacology 12/2014; · 4.65 Impact Factor
  • Source
    Dataset: ;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Several studies indicated that type 2 diabetes mellitus and insulin resistance are associated with increased colon cancer risk. Recently, studies suggest that metformin can reduce cancer risk in diabetic or non-diabetic patients with unclear mechanisms. This work aimed to determine the effect of metformin on chemically-induced colon cancer in mice. Colon cancer was induced using 1,2-dimethylhydrazine (DMH, 20 mg/kg/week, s.c.) for fifteen weeks. Experiment I: healthy mice were fed with basal diet for four weeks and then allocated into seven groups, (i) saline, (ii) DMH, (iii) oxaliplatin, (iv-v): metformin (100 or 200 mg/kg) and (vi-vii): oxaliplatin+metformin (100 or 200 mg/kg), respectively. Experiment II: type 2 diabetes mellitus was induced by injection of STZ (30 mg/kg) after four weeks of high-fat feeding and then mice were allocated into seven groups similar to those reported in experiment I. Examination of the colonic tissue at the end of the experiment highlighted an increase in angiogenic markers and cell proliferation and showed a greater immunostaining for insulin growth factor I receptors and CD34 in the colon of diabetic mice compared to non-diabetics. In general, metformin downregulated tumor angiogenesis and augmented the antitumor effect of oxaliplatin. Overall, the current results showed that metformin protected against DMH-induced colon cancer in non-diabetic and diabetic mice. This therapeutic effect was, at least in part, attributed to its anti-angiogenic and anti-proliferative mechanisms.
    PLoS ONE 06/2014; 9(6):e100562. · 3.53 Impact Factor

Full-text (2 Sources)

Download
15 Downloads
Available from
May 20, 2014