Insulin analogues display IGF-I-like mitogenic and anti-apoptotic activities in cultured cancer cells

Background: Insulin analogues are widely used in the treatment of diabetes mellitus. Some insulin analogues were reported to display atypical activities in vitro that resemble those of insulin-like growth factor-I (IGF-I). The aim of this study was to investigate whether two long-acting insulin analogues [glargine (Lantus, Sanofi Aventis, Germany) and detemir (Levemir, Novo Nordisk, Denmark)] and two short-acting analogues [lispro (Humalog, Eli Lilly, Indianapolis, USA) and aspart (Novolog, Novo Nordisk, Denmark)] exhibit IGF-I-like activities on cultured cancer cells in comparison with IGF-I and regular human insulin. Methods: HCT-116 (colorectal cancer), PC-3 (prostate cancer) and MCF-7 (breast adenocarcinoma) cell lines were treated with insulin, IGF-I or insulin analogues, and proliferation and protection from apoptosis were measured by cell counting and fluorescent-activated cell sorter (FACS) analysis, respectively. In addition, Western blots were used to identify signalling molecules activated by the analogues. Results: Glargine, detemir and lispro had proliferative effects that resemble IGF-I action. Insulin, however, did not stimulate cellular proliferation. In addition, glargine and detemir displayed an IGF-I-like anti-apoptotic activity. Glargine, like insulin and IGF-I, induced phosphorylation of both ERK and AKT, suggesting that the analogue is able to stimulate both the ras-raf-mitogen-activated protein kinase (MAPK) and PI3K-AKT pathways. Furthermore, glargine induced both insulin receptor (IR) and IGF-IR phosphorylation. Conclusions: Glargine, detemir and lispro, unlike regular insulin, exhibit in vitro proliferative and anti-apoptotic activities in a number of cancer cell lines. These actions resemble some of the effects of IGF-I, a growth factor involved in cancer initiation and progression. Insulin had no increased IGF-I activity. The specific receptor/s involved in mediating analogues actions remains to be identified.