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.
Weinstein
Doron
D
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Simon
Meital
M
Yehezkel
Einat
E
Laron
Zvi
Z
Werner
Haim
H
D000230:Adenocarcinoma; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007328:Insulin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000069057:Insulin Detemir; D000069036:Insulin Glargine; D061268:Insulin Lispro; D049528:Insulin, Long-Acting; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D011471:Prostatic Neoplasms; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000502:physiology*
D007328:Insulin; D061268:Insulin Lispro; D049528:Insulin, Long-Acting; D000069036:Insulin Glargine; D000069057:Insulin Detemir; D007334:Insulin-Like Growth Factor I