Inhibition of c-Met and prevention of spontaneous metastatic spreading by the 2-indolinone RPI-1.
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.
Cassinelli
Giuliana
G
Department of Experimental Oncology and Laboratories, Preclinical Chemotherapy and Pharmacology Unit, Istituto Nazionale Tumori, via Venezian 1, 20133 Milan, Italy.
Lanzi
Cinzia
C
Petrangolini
Giovanna
G
Tortoreto
Monica
M
Pratesi
Graziella
G
Cuccuru
Giuditta
G
Laccabue
Diletta
D
Supino
Rosanna
R
Belluco
Sara
S
Favini
Enrica
E
Poletti
Anna
A
Zunino
Franco
F
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D010766:Phosphorylation / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D007211:Indoles; C477359:RPI-1 compound; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met