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 IC 50 for proliferation ranged from 120 nmol/L (Colo205) to >8.5 Mmol/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 Ser 473 . At doses that inhibited proliferation, the compound also caused a G 0 -G 1 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. (Cancer Res 2006; 66(1): 362-71)

Ligand-Specific Antibodies to Insulin-Like Growth Factors Suppress Intestinal Polyp Formation in Apc+/− Mice

“…Thus, it is reasonable to consider that the antibodies to IGFs may have better specificity for tumors than antibodies to the IGF-IR. Second, IGF-IR has a homology with the insulin receptor; IGF-IR-blocking agents may cross-react with the insulin receptor and thus induce glucose intolerance (38)(39)(40)(41). However, because our antibodies do not cross-react with insulin in vitro, they are not expected to affect the blood glucose level.…”

Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer

“…Activity of the IGF-1R and the IR is associated with breast cancer tumorigenesis, and specific IGF-1R inhibitors show antitumoral effects against breast cancer (Mitsiades et al, 2004;Haluska et al, 2006). Thus, loss of klotho-mediated inhibition of the insulin/IGF-1 pathways may serve as a new mechanism involved in breast cancer tumorigenesis.…”

Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma

“…Since IGF-IR and the IR are structurally related, highly specific IGF-IR inhibitors are necessary to prevent diabetogenic effects in patients. Published IGF-IR-selective RTK-inhibitors are tyrphostins (AG538 [100,101] , AG1024 [102] , AG1034 [102] ), cyclolignans (picr opodophyllin [103,104] ), 6-5 ring-fused compounds [105] , pyrrole derivatives (NVP-AEW541 [106,107] , NVP-ADW742 [108,109] ), PQIP [110] , BMS536924 [111] , and BMS-554417 [112] . Antitumorigenic effects of some inhibitors on HCC cells have been demonstrated.…”