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Cisplatin resistance occurs, at least in part, through the function of the Fanconi anemia (FA)/BRCA pathway, a DNA-damage
response pathway required for repair of cisplatin cross-links. In the current study, we designed a cell-based screening strategy
to identify small-molecule inhibitors of the FA/BRCA pathway with the hypothesis that such molecules could restore sensitivity
to platinum agents. We identified four inhibitors, including three protein kinase inhibitors (wortmannin, H-9, and alsterpaullone)
and one natural compound (curcumin) that inhibit the FA/BRCA pathway. We show that curcumin, a compound that is generally
regarded as safe, inhibits the monoubiquitination of the FANCD2 protein as predicted by the screen and consequently sensitizes
ovarian and breast tumor cell lines to cisplatin through apoptotic cell death. We believe that this study shows an efficient,
high-throughput method for identifying new compounds that may sensitize cancer cells to DNA-damaging chemotherapy. [Mol Cancer
Ther 2006;5(4):952–61]