Chemosensitization to cisplatin by inhibitors of the Fanconi anemia/BRCA pathway.
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.
Chirnomas
Deborah
D
Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Taniguchi
Toshiyasu
T
de la Vega
Michelle
M
Vaidya
Ami P
AP
Vasserman
Maria
M
Hartman
Anne-Renee
AR
Kennedy
Richard
R
Foster
Rosemary
R
Mahoney
Jennifer
J
Seiden
Michael V
MV
D'Andrea
Alan D
AD
D000730:Androstadienes / Q000494:pharmacology; D019313:BRCA1 Protein / Q000187:drug effects / Q000502:physiology*; D001552:Benzazepines / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003474:Curcumin / Q000494:pharmacology*; D004249:DNA Damage; D005199:Fanconi Anemia / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D019313:BRCA1 Protein; D001552:Benzazepines; D007211:Indoles; D007546:Isoquinolines; D013449:Sulfonamides; C120793:alsterpaullone; C044388:N-(2-aminoethyl)-5-isoquinolinesulfonamide; D003474:Curcumin; D002945:Cisplatin; D000077191:Wortmannin