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Enhancing the activity of platinum-based drugs by improved inhibitors of ERCC1–XPF-mediated DNA repair

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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.

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Acknowledgements

This research was partly supported by funds from the Alberta Cancer Foundation. FG was supported by an Alberta Innovates scholarship and a Novartis Pharmaceuticals Canada Inc. scholarship. LPJ received funding from Olav Raagholt og Gerd Meidel Raagholts stiftelse for forskning. The authors are grateful to Bruno Chapuis and Denis Ressnikoff at CIQLE, Lyon for valuable assistance in image acquisition and analysis.

Author information

Author notes

  1. Francesco Gentile

    Present address: Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H 3Z6, Canada

Authors and Affiliations

  1. Department of Mechanical and Aerospace Engineering, Politecnico di Torino, 10129, Turin, Italy

    Gloria Ciniero, Marco A. Deriu & Jack A. Tuszynski

  2. Department of Chemistry, University of Alberta, Edmonton, AB, T6G 2G2, Canada

    Ahmed H. Elmenoufy & Frederick G. West

  3. Department of Pharmaceutical Chemistry, College of Pharmacy, Misr University for Science and Technology, P.O. Box: 77, 6th of October City, 12568, Egypt

    Ahmed H. Elmenoufy

  4. Department of Physics, University of Alberta, Edmonton, AB, T6G 2E1, Canada

    Francesco Gentile & Jack A. Tuszynski

  5. Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, T6G 1Z2, Canada

    Michael Weinfeld & Jack A. Tuszynski

  6. Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB, T6G 2E1, Canada

    Michael Weinfeld & Frederick G. West

  7. 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

    Charles Dumontet, Emeline Cros-Perrial & Lars Petter Jordheim

  8. Laboratoire de Biochimie-Toxicologie, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, 69495, Pierre Bénite, France

    Charles Dumontet

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  1. Gloria Ciniero
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Ciniero, G., Elmenoufy, A.H., Gentile, F. et al. Enhancing the activity of platinum-based drugs by improved inhibitors of ERCC1–XPF-mediated DNA repair. Cancer Chemother Pharmacol 87, 259–267 (2021). https://doi.org/10.1007/s00280-020-04213-x

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