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

Giuliana Cassinelli, Cinzia Lanzi, Giovanna Petrangolini, Monica Tortoreto, Graziella Pratesi, Giuditta Cuccuru, Diletta Laccabue, Rosanna Supino, Sara Belluco, Enrica Favini, Anna Poletti, Franco Zunino

Research output: Contribution to journalArticle

Abstract

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

Original languageEnglish
Pages (from-to)2388-2397
Number of pages10
JournalMolecular Cancer Therapeutics
Volume5
Issue number9
DOIs
Publication statusPublished - Sep 2006

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Fingerprint Dive into the research topics of 'Inhibition of c-Met and prevention of spontaneous metastatic spreading by the 2-indolinone RP-1'. Together they form a unique fingerprint.

  • Cite this

    Cassinelli, G., Lanzi, C., Petrangolini, G., Tortoreto, M., Pratesi, G., Cuccuru, G., Laccabue, D., Supino, R., Belluco, S., Favini, E., Poletti, A., & Zunino, F. (2006). Inhibition of c-Met and prevention of spontaneous metastatic spreading by the 2-indolinone RP-1. Molecular Cancer Therapeutics, 5(9), 2388-2397. https://doi.org/10.1158/1535-7163.MCT-06-0245