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Research Articles: Therapeutics, Targets, and Development

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

¹ First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan; ² Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Lung Institute, Seoul National University College of Medicine, Seoul, Korea; and ³ Vanderbilt-Ingram Cancer Center and Departments of Medicine and Cell Biology, Vanderbilt University, Nashville, Tenessee

Requests for reprints: Yasushi Adachi, First Department of Internal Medicine, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo 060-8543, Japan. Phone: 81-11-611-2111, ext. 3211; Fax: 81-11-611-2282. E-mail: yadachi{at}sapmed.ac.jp

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. [Mol Cancer Ther 2008;7(6):1483–93]

Grant support: Ministry of Education, Culture, Sports, Science, and Technology and Ministry of Health, Labour and Welfare, Japan, grants-in-aid and Vanderbilt SPORE in Lung Cancer grant CA90949.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: W. Piao, Y. Wang, and Y. Adachi contributed equally to this work.

⁴ Developed at the NIH and available on the Internet at http://rsb.info.nih.gov/nih-image/.

Received 12/13/07; revised 4/ 2/08; accepted 4/ 9/08.