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  • Title: Farnesyltransferase inhibitor FTI-277 prevents autocrine growth stimulation of neuroblastoma by BDNF.
    Author: Girgert R, Wittrock J, Pfister S, Schweizer P.
    Journal: J Cancer Res Clin Oncol; 2003 Apr; 129(4):227-33. PubMed ID: 12700894.
    Abstract:
    PURPOSE: Autocrine growth stimulation by IGF-II and BDNF is frequently observed in neuroblastoma. The signals of the receptors of these growth factors are transduced to the nucleus via the Ras-MAP-kinase pathway where they induce proliferation. Inactivation of Ras-proteins by farnesyltransferase inhibitors such as FTI-277 disrupts growth stimulation of ras-transformed cells. We investigated whether FTI-277 is also active against tumor cells with constitutively activated growth factor receptors but lacking ras-mutations. METHOD: We analyzed eight different neuroblastoma cell lines for the expression of BDNF and its receptor trkB. Two of these cell lines with a complete autocrine BDNF loop were treated with FTI-277, and the effects of Ras-inactivation on the signal transduction of BDNF were analyzed. RESULTS: Treatment of neuroblastoma cells with 10 microM FTI-277 for 4 days reduced the amount of membrane-bound Ras-protein to almost 50%. Activation of MAP-kinase, induction of N-myc expression, and proliferation were clearly reduced in the treated cells. In addition, we observed some cytotoxic effects of FTI-277 accompanied by morphological changes of the neuroblastoma cells and a delayed induction of apoptosis. CONCLUSION: Farnesyltransferase inhibitors are active against neuroblastoma cells but the mechanism of action is not limited to inactivation of Ras. Further investigations on the targets of FTI-277 are recommended.
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