2002 CTOS Annual Meeting Oral Presentations — Biology

TARGETING MET ONCOGENE IN HUMAN OSTEOSARCOMA BY K-252A TYROSINE-KINASE INHIBITOR: A NEW THERAPEUTIC APPROACH
[Abstract ID: 71]

Category: Biology

Presentation: Young Investigator

Authors: Sofia Avnet¹, Francesca Perut¹, Riccardo Ferracini², Maria Flavia Di Renzo², Nicola Baldini¹

Author Institutions: ¹Laboratory of Pathophysiology Istituto Ortopedico Rizzoli Bologna, Italy; ²Laboratory of Cancer Genetics Institute for Cancer Research and Treatment Candiolo, Italy

Presenter: Sofia Avnet
sofia.avnet@ior.it

Correspondent: Nicola Baldini
nicola.baldini@ior.it
Bologna Italy 40136
Ph: +39.(0)50.6366678
Fax: +39.(0)50.6366748

Objectives: Activation of Met, the tyrosine kinase receptor for HGF/SF, induces downstream signalling pathways that trigger a number of cell functions, including proliferation, motility, invasiveness, and metastatic ability in a variety of neoplasms. Met is overexpressed in osteosarcoma, in association with an aggressive behavior of this tumor, both in vitro and in a clinical setting. We evaluated the ability of a natural alkaloid (K252a) which acts as a kinase inhibitor, by competing with the binding of ATP to the catalitic domain of Met, to interfere with the growth of human osteosarcoma cells, as a preliminary step toward the development of innovative therapeutic strategies for this tumor.

Methods: We evaluated the level of Met expression by Western blotting in human osteosarcoma cell lines (U-2 OS, MG-63, Saos-2), that are representative of different levels of differentiation and aggressiveness of osteosarcoma. IC50 was analyzed at different concentrations of K252a (50-2000 ng/ml).

Results: In osteosarcoma cells, the level of Met expression was associated with the ability of K252a to inhibit cell growth. In fact, the IC50 of K252a was 420 ng/ml in Saos-2, the more differentiated cell line with the lowest expression of Met, whereas it was 55.8 ng/ml in U-2 OS, the cell line with the lowest differentiated phenotype and the highest Met levels. Intermediate values (IC50, 190.7 ng/ml) were found in MG63.

Conclusions: K252a is a potent inhibitor of proliferation of human osteosarcoma, and its effects are positively associated with the level of expression of Met, but inversely related to the differentiative status of the tumor.