RESULTS: Through a cell-based screening assay of over 16,000 chemicals, we identified 26 small molecules that inhibit ionizing radiation and
cisplatin-induced FANCD2 foci formation, a marker of FA pathway activity, in multiple human cell lines. Most of these small molecules also compromised ionizing radiation-induced RAD51 foci formation and homologous recombination repair, indicating that they are not selective toward the regulation of FANCD2. These compounds include known inhibitors of the
proteasome,
cathepsin B, lysosome, CHK1, HSP90, CDK and PKC, and several uncharacterized chemicals including a novel
proteasome inhibitor (Chembridge compound 5929407).Isobologram analyses demonstrated that half of the identified molecules sensitized
ovarian cancer cells to
cisplatin. Among them, 9 demonstrated increased efficiency toward FA pathway-proficient,
cisplatin-resistant
ovarian cancer cells. Six small molecules, including
bortezomib (
proteasome inhibitor), CA-074-Me (
cathepsin B inhibitor) and
17-AAG (HSP90 inhibitor), synergized with
cisplatin specifically in FA-proficient
ovarian cancer cells (2008 + FANCF), but not in FA-deficient isogenic cells (2008). In addition,
geldanamycin (HSP90 inhibitor) and two CHK1 inhibitors (
UCN-01 and SB218078) exhibited a significantly stronger synergism with
cisplatin in FA-proficient cells when compared to FA-deficient cells, suggesting a contribution of their FA pathway inhibitory activity to
cisplatin sensitization.
CONCLUSION: Our findings suggest that, despite their lack of specificity, pharmaceutical inhibition of the FA pathway by
bortezomib, CA-074-Me, CHK1 inhibitors or HSP90 inhibitors may be a promising strategy to sensitize
cisplatin-resistant, FA pathway-proficient
tumor cells to
cisplatin. In addition, we identified four new small molecules which synergize with
cisplatin. Further development of their analogs and evaluation of their combination with
cisplatin may lead to the development of efficient
cancer treatments.