Gloria Ciniero1, Ahmed H Elmenoufy2,3, Francesco Gentile4,5, Michael Weinfeld6,7, Marco A Deriu1, Frederick G West2,7, Jack A Tuszynski1,4,6, Charles Dumontet8,9, Emeline Cros-Perrial8, Lars Petter Jordheim10. 1. Department of Mechanical and Aerospace Engineering, Politecnico di Torino, 10129, Turin, Italy. 2. Department of Chemistry, University of Alberta, Edmonton, AB, T6G 2G2, Canada. 3. Department of Pharmaceutical Chemistry, College of Pharmacy, Misr University for Science and Technology, P.O. Box: 77, 6th of October City, 12568, Egypt. 4. Department of Physics, University of Alberta, Edmonton, AB, T6G 2E1, Canada. 5. Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H 3Z6, Canada. 6. Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, T6G 1Z2, Canada. 7. Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB, T6G 2E1, Canada. 8. Univ Lyon, Université Claude Bernard Lyon 1, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, 8 Avenue Rockefeller, 69008, Lyon, France. 9. Laboratoire de Biochimie-Toxicologie, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, 69495, Pierre Bénite, France. 10. Univ Lyon, Université Claude Bernard Lyon 1, Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, 8 Avenue Rockefeller, 69008, Lyon, France. lars-petter.jordheim@univ-lyon1.fr.
Abstract
PURPOSE: The ERCC1-XPF 5'-3' DNA endonuclease complex is involved in the nucleotide excision repair pathway and in the DNA inter-strand crosslink repair pathway, two key mechanisms modulating the activity of chemotherapeutic alkylating agents in cancer cells. Inhibitors of the interaction between ERCC1 and XPF can be used to sensitize cancer cells to such drugs. METHODS: We tested recently synthesized new generation inhibitors of this interaction and evaluated their capacity to sensitize cancer cells to the genotoxic activity of agents in synergy studies, as well as their capacity to inhibit the protein-protein interaction in cancer cells using proximity ligation assay. RESULTS: Compound B9 showed the best activity being synergistic with cisplatin and mitomycin C in both colon and lung cancer cells. Also, B9 abolished the interaction between ERCC1 and XPF in cancer cells as shown by proximity ligation assay. Results of different compounds correlated with values from our previously obtained in silico predictions. CONCLUSION: Our results confirm the feasibility of the approach of targeting the protein-protein interaction between ERCC1 and XPF to sensitize cancer cells to alkylating agents, thanks to the improved binding affinity of the newly synthesized compounds.
PURPOSE: The ERCC1-XPF 5'-3' DNA endonuclease complex is involved in the nucleotide excision repair pathway and in the DNA inter-strand crosslink repair pathway, two key mechanisms modulating the activity of chemotherapeutic alkylating agents in cancer cells. Inhibitors of the interaction between ERCC1 and XPF can be used to sensitize cancer cells to such drugs. METHODS: We tested recently synthesized new generation inhibitors of this interaction and evaluated their capacity to sensitize cancer cells to the genotoxic activity of agents in synergy studies, as well as their capacity to inhibit the protein-protein interaction in cancer cells using proximity ligation assay. RESULTS: Compound B9 showed the best activity being synergistic with cisplatin and mitomycin C in both colon and lung cancer cells. Also, B9 abolished the interaction between ERCC1 and XPF in cancer cells as shown by proximity ligation assay. Results of different compounds correlated with values from our previously obtained in silico predictions. CONCLUSION: Our results confirm the feasibility of the approach of targeting the protein-protein interaction between ERCC1 and XPF to sensitize cancer cells to alkylating agents, thanks to the improved binding affinity of the newly synthesized compounds.
Entities:
Keywords:
Cancer; Chemical synthesis; DNA repair; Protein–protein interaction
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