This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Cassinelli, G. Articles by Zunino, F. Search for Related Content PubMed PubMed Citation Articles by Cassinelli, G. Articles by Zunino, F.

Research Articles: Therapeutics

Inhibition of c-Met and prevention of spontaneous metastatic spreading by the 2-indolinone RPI-1

¹ Department of Experimental Oncology and Laboratories, Preclinical Chemotherapy and Pharmacology Unit, Istituto Nazionale Tumori; and ² Department of Veterinary Pathology, University of Milan, Milan, Italy

Requests for reprints: Cinzia Lanzi, Istituto Nazionale Tumori, via Venezian 1, 20133 Milan, Italy. Phone: 39-02-23902627; Fax: 39-02-23902692. E-mail: cinzia.lanzi{at}istitutotumori.mi.it

Hepatocyte growth factor (HGF) and its tyrosine kinase receptor Met play a pivotal role in the tumor metastatic phenotype and represent attractive therapeutic targets. We investigated the biochemical and biological effects of the tyrosine kinase inhibitor RPI-1 on the human lung cancer cell lines H460 and N592, which express constitutively active Met. RPI-1-treated cells showed down-regulation of Met activation and expression, inhibition of HGF/Met-dependent downstream signaling involving AKT, signal transducers and activators of transcription 3 and paxillin, as well as a reduced expression of the proangiogenic factors vascular endothelial growth factor and basic fibroblast growth factor. Cell growth in soft agar of H460 cells was strongly reduced in the presence of the drug. Furthermore, RPI-1 inhibited both spontaneous and HGF-induced motility/invasiveness of both H460 and human endothelial cells. Targeting of Met signaling by alternative methods (Met small interfering RNA and anti-phosphorylated Met antibody intracellular transfer) produced comparable biochemical and biological effects. Using the spontaneously metastasizing lung carcinoma xenograft H460, daily oral treatment with well-tolerated doses of RPI-1 produced a significant reduction of spontaneous lung metastases (–75%; P < 0.001, compared with control mice). In addition, a significant inhibition of angiogenesis in primary s.c. tumors of treated mice was observed, possibly contributing to limit the development of metastases. The results provide preclinical evidence in support of Met targeting pharmacologic approach as a new option for the control of tumor metastatic dissemination. [Mol Cancer Ther 2006;5(9):2388–97]

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.

Received 5/ 3/06; revised 6/22/06; accepted 7/11/06.