Insulin-like growth factor-I receptor blockade by a specific tyrosine kinase inhibitor for human gastrointestinal carcinomas

Wenhua Piao, Yu Wang, Yasushi Adachi, Hiroyuki Yamamoto, Rong Li, Arisa Imsumran, Hua Li, Tadateru Maehata, Masanori Ii, Yoshiaki Arimura, Choon Taek Lee, Yasuhisa Shinomura, David P. Carbone, Kohzoh Imai

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36 Citations (Scopus)

Abstract

Insulin-like growth factor-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of gastrointestinal (GI) cancers. In this study, we sought to evaluate the effect of a new tyrosine kinase inhibitor of IGF-IR, NVP-AEW541, on the signal transduction and the progression of GI carcinomas. We assessed the effect of NVP-AEW541 on signal transduction, proliferation, survival, and migration in four GI cancer cells: colorectal adenocarcinoma HT29, pancreatic adenocarcinoma BxPC3, esophageal squamous cell carcinoma TE1, and hepatoma PLC/PRF/5. The effects of NVP-AEW541 alone and with chemotherapy were studied in vitro and in nude mouse xenografts. We also analyzed the effects of NVP-AEW541 on insulin signals and hybrid receptor formation between IGF-IR and insulin receptor. NVP-AEW541 blocked autophosphorylation of IGF-IR and both Akt and extracellular signal-regulated kinase activation by IGF but not by insulin. NVP-AEW541 suppressed proliferation and tumorigenicity in vitro in a dose-dependent manner in all cell lines. The drug inhibited tumor as a single agent and, when combined with stressors, up-regulated apoptosis in a dose-dependent fashion and inhibited mobility. NVP-AEW541 augmented the effects of chemotherapy on in vitro growth and induction of apoptosis. Moreover, the combination of NVP-AEW541 and chemotherapy was highly effective against tumors in mice. This compound did not influence hybrid receptor formation. Thus, NVP-AEW541 may have significant therapeutic utility in human GI carcinomas both alone and in combination with chemotherapy.

Original languageEnglish
Pages (from-to)1483-1493
Number of pages11
JournalMolecular cancer therapeutics
Volume7
Issue number6
DOIs
Publication statusPublished - 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Piao, W., Wang, Y., Adachi, Y., Yamamoto, H., Li, R., Imsumran, A., Li, H., Maehata, T., Ii, M., Arimura, Y., Lee, C. T., Shinomura, Y., Carbone, D. P., & Imai, K. (2008). Insulin-like growth factor-I receptor blockade by a specific tyrosine kinase inhibitor for human gastrointestinal carcinomas. Molecular cancer therapeutics, 7(6), 1483-1493. https://doi.org/10.1158/1535-7163.MCT-07-2395