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In vitro and in vivo antitumor effects of the dual insulin-like growth factor-I/insulin receptor inhibitor, BMS-554417.
Cancer Res. 2006 Jan 01; 66(1):362-71.CR

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+Show Affiliations

Division of Medical Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16397250

Citation

Haluska, Paul, et al. "In Vitro and in Vivo Antitumor Effects of the Dual Insulin-like Growth factor-I/insulin Receptor Inhibitor, BMS-554417." Cancer Research, vol. 66, no. 1, 2006, pp. 362-71.
Haluska P, Carboni JM, Loegering DA, et al. In vitro and in vivo antitumor effects of the dual insulin-like growth factor-I/insulin receptor inhibitor, BMS-554417. Cancer Res. 2006;66(1):362-71.
Haluska, P., Carboni, J. M., Loegering, D. A., Lee, F. Y., Wittman, M., Saulnier, M. G., Frennesson, D. B., Kalli, K. R., Conover, C. A., Attar, R. M., Kaufmann, S. H., Gottardis, M., & Erlichman, C. (2006). In vitro and in vivo antitumor effects of the dual insulin-like growth factor-I/insulin receptor inhibitor, BMS-554417. Cancer Research, 66(1), 362-71.
Haluska P, et al. In Vitro and in Vivo Antitumor Effects of the Dual Insulin-like Growth factor-I/insulin Receptor Inhibitor, BMS-554417. Cancer Res. 2006 Jan 1;66(1):362-71. PubMed PMID: 16397250.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro and in vivo antitumor effects of the dual insulin-like growth factor-I/insulin receptor inhibitor, BMS-554417. AU - Haluska,Paul, AU - Carboni,Joan M, AU - Loegering,David A, AU - Lee,Francis Y, AU - Wittman,Mark, AU - Saulnier,Mark G, AU - Frennesson,David B, AU - Kalli,Kimberly R, AU - Conover,Cheryl A, AU - Attar,Ricardo M, AU - Kaufmann,Scott H, AU - Gottardis,Marco, AU - Erlichman,Charles, PY - 2006/1/7/pubmed PY - 2006/2/24/medline PY - 2006/1/7/entrez SP - 362 EP - 71 JF - Cancer research JO - Cancer Res VL - 66 IS - 1 N2 - 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. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/16397250/In_vitro_and_in_vivo_antitumor_effects_of_the_dual_insulin_like_growth_factor_I/insulin_receptor_inhibitor_BMS_554417_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=16397250 DB - PRIME DP - Unbound Medicine ER -