Inhibition of cell signaling by the combi-nitrosourea FD137 in the androgen independent DU145 prostate cancer cell line |
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Authors: | Qiu Qiyu Dudouit Fabienne Banerjee Ranjita McNamee James P Jean-Claude Bertrand J |
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Affiliation: | Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Royal Victoria Hospital, Montreal, Quebec, Canada. |
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Abstract: | BACKGROUND: FD137, a nitrosourea appended to a quinazoline ring, was designed to simultaneously block epidermal growth factor receptor (EGFR)-mediated signaling and damage genomic DNA in refractory EGF-dependent prostate tumors. METHODS: The mixed inhibition of cell signaling and DNA damage by FD137 were determined by Western blotting, RT-PCR, flow cytometry, sulforhodamine B (SRB), and comet assay. RESULTS: FD137 and its metabolite FD110 induced a dose-dependent increase in inhibition of EGF-stimulated EGFR autophosphorylation and this translated into blockade of c-fos gene expression in DU145 cells. FD137 induced significant levels of DNA damage and showed 150-fold greater anti-proliferative activity than BCNU, a classical nitrosourea. In contrast to BCNU, complete inhibition of EGF-induced cell transition to S-phase was observed at concentrations of FD137 as low as 3 microM. CONCLUSION: FD137 could not only damage DNA, but also significantly block downstream EGFR-mediated signaling. The superior activity of FD137 may be imputable to the combined effect of its mixed EGFR/DNA targeting properties. This novel strategy may well represent a new approach to target nitrosoureas to EGFR-overexpressing carcinomas of the prostate. |
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Keywords: | nitrosourea EGFR BCNU signal transduction DNA damage prostate cancer |
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