ABSTRACT
Some of the latest fi ndings in ionizing radiation (IR)- or cisplatin-induced FANCD2 foci formation screening assays suggest a diverse spectrum of pathways to sensitize cancer cells to cisplatin (Jacquemont et al. 2012). Human cells transfected with Green Fluorescent Protein (EGFP)-FANCD2 were treated with compounds from chemical libraries and exposed to IR to induce FANCD2 foci formation. Positive hits showing a signifi cant decrease in EGFP-FANCD2 foci formation were confi rmed in multiple human cell lines. The majority of the small molecules identifi ed from the screen also showed decreased IR-induced RAD51 foci and lower homologous recombinational repair, indicating an effect that was not specifi c to FANCD2. The compounds identifi ed showed pharmacological inhibition of the proteasome, cathepsin B, lysosome, CHK1, HSP90, CDK, and PKC. Among those compounds identifi ed, inhibitors of proteasome, cathepsin B, and HSP behaved in a synergistic manner with cisplatin that was dependent on an intact FA pathway. These fi ndings suggest that actual inhibition of the FA pathway is required for small molecule sensitization to cisplatin. Moreover, it brings to light the opportunity for the development of compounds that would render cisplatin-resistant FA pathway-profi cient tumors vulnerable to cisplatin and related cross-linking agents.
