Treatment with Insulin Analog X10 and IGF-1 Increases Growth of Colon Cancer Allografts.
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.
Full-textDOI: · Available from: Bo Falck Hansen, Mar 05, 2014
- SourceAvailable from: Jan Willem van der Laan[Show abstract] [Hide abstract]
ABSTRACT: Insulin analogues are structurally modified molecules with altered pharmaco-kinetic and -dynamic properties compared to regular human insulin used by diabetic patients. While these compounds are tested for undesired mitogenic effects, an epidemiological discussion is ongoing regarding an association between insulin analogue therapy and increased cancer incidence, including breast cancer. Standard in vivo rodent carcinogenesis assays do not pick up this possible increased carcinogenic potential. Here we studied the role of insulin analogues in breast cancer development. For this we used the human relevant mammary gland specific p53(R270H/+)WAPCre mouse model. Animals received life long repeated treatment with four different insulin (-like) molecules: normal insulin, insulin glargine, insulin X10 (AspB10) or insulin-like growth factor 1 (IGF1). Insulin-like molecules with strong mitogenic signaling, insulin X10 and IGF1, significantly decreased the time for tumor development. Yet, insulin glargine and normal insulin, did not significantly decrease the latency time for (mammary gland) tumor development. The majority of tumors had an epithelial to mesenchymal transition phenotype (EMT), irrespective of treatment condition. Enhanced extracellular signaling related kinase (Erk) or serine/threonine kinase (Akt) mitogenic signaling was in particular present in tumors from the insulin X10 and IGF1 treatment groups. These data indicate that insulin-like molecules with enhanced mitogenic signaling increase the risk of breast cancer development. Moreover, the use of a tissue specific cancer model, like the p53(R270H/+)WAPCre mouse model, is relevant to assess the intrinsic pro-carcinogenic potential of mitogenic and non-mitogenic biologicals such as insulin analogues.Breast cancer research: BCR 12/2015; 17(1):518. DOI:10.1186/s13058-015-0518-y · 5.88 Impact Factor
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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; 93(4). DOI:10.1016/j.bcp.2014.12.006 · 4.65 Impact Factor
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ABSTRACT: Purpose: Conflicting data exist on the interaction of diabetes mellitus with outcomes in patients with renal cell carcinoma. We evaluated the association of diabetes mellitus with survival in patients with clear cell renal cell carcinoma treated with nephrectomy. Materials and Methods: We reviewed the records of 1,964 patients treated surgically for sporadic, unilateral, M0 clear cell renal cell carcinoma between 1990 and 2008. One pathologist re-reviewed all specimens to confirm clear cell renal cell carcinoma. We matched 257 patients with diabetes 1:2 to referent patients without diabetes according to clinicopathological and surgical features. Cancer specific and overall survival was estimated using the Kaplan-Meier method. Cox models were used to evaluate associations with outcomes. Results: A total of 257 patients (13%) had diabetes mellitus. They were significantly older and more likely to be obese, and had higher Charlson scores, renal impairment and smoking rates, and worse performance status at surgery (p <0.001). Pathological features were similar between the groups. Median postoperative followup was 8.7 years. Five-year cancer specific survival was similar in patients with and without diabetes (82% vs 86%, p = 0.1) while 5-year overall survival was significantly worse in those with diabetes (65% vs 74%, p <0.001). On multivariable analysis diabetes mellitus independently predicted cancer specific mortality (HR 1.55, 95% CI 1.08-2.21, p = 0.02) and all-cause mortality (HR 1.32, 95% CI 1.06-1.64, p = 0.01). Conclusions: Our results suggest that diabetes mellitus is independently associated with decreased cancer specific and overall survival in patients with surgically treated clear cell renal cell carcinoma.The Journal of Urology 06/2014; 192(6). DOI:10.1016/j.juro.2014.06.014 · 3.75 Impact Factor