Inhibition of transforming activity of the ret/ptc1 oncoprotein by a 2- indolinone derivative

Cinzia Lanzi, Giuliana Cassinelli, Tiziana Pensa, Marco Cassinis, Romolo A. Gambetta, Maria G. Borrello, Ernesto Menta, Marco A. Pierotti, Franco Zunino

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ret-derived oncogenes are frequently and specifically expressed in thyroid tumors. In contrast to the ret receptor, ret oncoproteins are characterized by ligand-independent tyrosine-kinase activity and tyrosine phosphorylation. In this study, novel synthetic arylidene 2-indolinone compounds were evaluated as inhibitors of the ret/ptc I tyrosine kinase. Four compounds inhibited ret/ptc1 activity in immunokinase assay (IC50 27-42 μM) including one (1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl)methylene)- 2H-indol-2-one) (Cpd I) that selectively inhibited the anchorage-independent growth of NIH3T3 transformants expressing the ret/ptc1 gene (NIH3T3(Ptc1) cells). Following exposure to Cpd I, the transformed phenotype of NIH3T3(Ptc1) cells was reverted, within 24 hr, to a normal fibroblast-like morphology in adherent-cell culture. In these cells, the constitutive tyrosine phosphorylation of ret/ptc1, of the transducing adaptor protein shc and of a series of co-immunoprecipitated peptides became much reduced, as demonstrated by immunoprecipitation/Western-blot analyses. Data presented provide additional evidence that ret/ptc1 is directly implicated in malignant transformation, and demonstrate the ability of Cpd I to interfere in the signal transduction pathway constitutively activated by the ret/ptc1 oncoprotein. These results confirm the interest of the arylidene 2-indolinone class of tyrosine-kinase inhibitors as tools for the study of ret signaling and the control of cell proliferation in ret- and ret/ptcs-associated diseases.

Original languageEnglish
Pages (from-to)384-390
Number of pages7
JournalInternational Journal of Cancer
Issue number3
Publication statusPublished - 2000

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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