In vitro and in vivo antitumor effects of the dual insulin-like growth factor-I/insulin receptor inhibitor, BMS-554417.
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.
Haluska
Paul
P
Division of Medical Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Carboni
Joan M
JM
Loegering
David A
DA
Lee
Francis Y
FY
Wittman
Mark
M
Saulnier
Mark G
MG
Frennesson
David B
DB
Kalli
Kimberly R
KR
Conover
Cheryl A
CA
Attar
Ricardo M
RM
Kaufmann
Scott H
SH
Gottardis
Marco
M
Erlichman
Charles
C
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011728:Pyridones / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016196:S Phase / Q000187:drug effects
D000970:Antineoplastic Agents; C507943:BMS-554417; D010879:Piperazines; D011728:Pyridones; D019938:Cyclin D1; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D020169:Caspases