Poster Presenter

Inhibition Of Protein Interaction Sensitizes The Activity Of Cytotoxic Platinum Compounds
Pierre Juban, Kevin Bardin, Emeline Cros-Perrial, Charles Dumontet & Lars Petter Jordheim
France

The antitumoral activity of cytotoxic platinum derivatives is limited by the repair of DNA adducts by the nucleotide excision repair (NER). NER involves several proteins whose physical interaction is crucial for correct DNA repair. We hypothesize that the inhibition of the interaction between the proteins ERCC1, XPF and XPA would sensitize cancer cells to platinum compounds.

We stably and transiently transfected plasmids coding the interacting domains of the proteins into human lung cancer cells (A549) and evaluated the cytotoxicity of platinum compounds. Cells transiently expressing the domain of ERCC1 interacting with XPA were 1.5-fold more sensitive to cisplatin (IC50 = 11.9 µM vs. 18.3 µM). Stable expression of domains of ERCC1 interacting with XPA or XPF, or the domains of XPA or XPF interacting with ERCC1, induced 1.7-2.2-fold sensitization of cells to carboplatin. No differences were observed with other compounds or different schemes of exposure.

Our results show that the modification of protein interaction in NER can alter the activity of platinum-based chemotherapy. We are currently searching for molecular inhibitors of these interactions.