Abstract Title:

Chemosensitization to cisplatin by inhibitors of the Fanconi anemia/BRCA pathway.

Abstract Source:

Mol Cancer Ther. 2006 Apr;5(4):952-61. PMID: 16648566

Abstract Author(s):

Deborah Chirnomas, Toshiyasu Taniguchi, Michelle de la Vega, Ami P Vaidya, Maria Vasserman, Anne-Renee Hartman, Richard Kennedy, Rosemary Foster, Jennifer Mahoney, Michael V Seiden, Alan D D'Andrea

Article Affiliation:

Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.


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.

Study Type : In Vitro Study

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