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.

Role of Metformin in Suppressing 1,2-Dimethylhydrazine-Induced Colon Cancer in Diabetic and Non-Diabetic Mice: Effect on Tumor Angiogenesis and Cell Proliferation

“…It has been reported that treatment with IGF-I significantly increased the growth of MC38 cell allograft in mice with diet induced obesity [41]. Similarly, it was found that IGF increases cell proliferation in pancreatic tumors [42] and activation of the IGFR-I by IGF-I is associated with the risk and progression of many types of cancer [43].…”

Diabetes Mellitus is Independently Associated with an Increased Risk of Mortality in Patients with Clear Cell Renal Cell Carcinoma

“…5 High plasma insulin results in increased hepatic production of IGF-1, which has a central driving role in cell proliferation and differentiation, protecting against apoptosis. 24 Over expression of IGF-1 and IGF-1 receptor was associated with an increased risk of prostate, cervical, ovarian, breast and colon cancers in clinical studies, 5,25 and with increased tumor growth in vitro 26 and in animal models. 27 Furthermore, there is growing understanding of the role of metabolic dysregulation and reliance on aerobic glycolysis in RCC pathogenesis, known as the Warburg effect.…”

Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality

“…One such analog that is not in clinical use is known as AspB10, as it has an amino acid substitution of aspartic acid in place of histidine at position 10 on the B chain of insulin. This insulin analog was found to induce spontaneous mammary tumors in rats and has subsequently been shown to be mitogenic in human breast cancer cells in vitro (135) and in animal models of breast and colon cancer (59,85). Human registry studies and retrospective cohort studies published in 2011-2012 reported that other insulin analogs may increase the risk of certain cancers, including breast cancer (74,165,179).…”