In vitro and in vivo antitumor effects of the dual insulin-like growth factor-I/insulin receptor inhibitor, BMS-554417.

Abstract

The insulin-like growth factor receptor (IGF-IR) and insulin receptor are either overactivated and/or overexpressed in a wide range of tumor types and contribute to tumorigenicity, proliferation, metastasis, and drug resistance. Here, we show that BMS-554417, a novel small molecule developed as an inhibitor of IGF-IR, inhibits IGF-IR and insulin receptor kinase activity and proliferation in vitro, and reduces tumor xenograft size in vivo. In a series of carcinoma cell lines, the IC50 for proliferation ranged from 120 nmol/L (Colo205) to >8.5 micromol/L (OV202). The addition of stimulatory ligands was unnecessary for the antiproliferative effect in MCF-7 and OV202 cells. BMS-554417 treatment inhibited IGF-IR and insulin receptor signaling through extracellular signal-related kinase as well as the phosphoinositide 3-kinase/Akt pathway, as evidenced by decreased Akt phosphorylation at Ser473. At doses that inhibited proliferation, the compound also caused a G0-G1 arrest and prevented nuclear accumulation of cyclin D1 in response to LR3 IGF-I. In Jurkat T-cell leukemia cells, this agent triggered apoptotic cell death via the mitochondrial pathway. BMS-554417 was orally bioavailable and significantly inhibited the growth of IGF1R-Sal tumor xenografts in vivo. BMS-554417 is a member of a novel class of IGF-IR/insulin receptor inhibitors that have potential clinical applications because of their antiproliferative and proapoptotic activity in vitro and in vivo.

• Authors: Paul Haluska, Joan M Carboni, David A Loegering, Francis Y Lee, Mark Wittman, Mark G Saulnier, David B Frennesson, Kimberly R Kalli, Cheryl A Conover, Ricardo M Attar, Scott H Kaufmann, Marco Gottardis, Charles Erlichman
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 1 Pg. 362-71 (Jan 01 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16397250 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• BMS-554417
• Piperazines
• Pyridones
• Cyclin D1
• Insulin-Like Growth Factor I
• Receptor, IGF Type 1
• Receptor, Insulin
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinase Kinases
• Caspases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, metabolism)
• Caspases (metabolism)
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cyclin D1 (metabolism)
• Dose-Response Relationship, Drug
• Enzyme Activation
• Female
• G1 Phase (drug effects)
• Humans
• Insulin-Like Growth Factor I (antagonists & inhibitors)
• Mice
• Mice, Nude
• Mitochondria (drug effects, physiology)
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors, metabolism)
• Ovarian Neoplasms (drug therapy, metabolism)
• Phosphorylation (drug effects)
• Piperazines (pharmacology)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Pyridones (pharmacology)
• Receptor, IGF Type 1 (antagonists & inhibitors, metabolism)
• Receptor, Insulin (antagonists & inhibitors, metabolism)
• S Phase (drug effects)