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

Piao, Wenhua, Wang, Yu, Adachi, Yasushi, Yamamoto, Hiroyuki, Li, Rong, Imsumran, Arisa, Li, Hua, Maehata, Tadateru, Ii, Masanori, Arimura, Yoshiaki, Lee, Choon-Taek, Shinomura, Yasuhisa, Carbone, David P and Imai, Kohzoh (2008) Insulin-like growth factor-I receptor blockade by a specific tyrosine kinase inhibitor for human gastrointestinal carcinomas. Molecular cancer therapeutics, 7 (6). pp. 1483-1493. ISSN 1535-7163


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.

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Additional Information: author can archive post-print (ie final draft post-refereeing); Authors final version may be deposited on institutional website/ repository if required by institution
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14


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