Skip to main content
Erschienen in: Cancer Chemotherapy and Pharmacology 2/2021

05.01.2021 | Original Article

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

verfasst von: Gloria Ciniero, Ahmed H. Elmenoufy, Francesco Gentile, Michael Weinfeld, Marco A. Deriu, Frederick G. West, Jack A. Tuszynski, Charles Dumontet, Emeline Cros-Perrial, Lars Petter Jordheim

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 2/2021

Einloggen, um Zugang zu erhalten

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.
Literatur
4.
Zurück zum Zitat Heyza JR, Arora S, Zhang H, Conner KL, Lei W, Floyd AM, Deshmukh RR, Sarver J, Trabbic CJ, Erhardt P, Chan TH, Dou QP, Patrick SM (2018) Targeting the DNA repair endonuclease ERCC1–XPF with green tea polyphenol epigallocatechin-3-gallate (EGCG) and its prodrug to enhance cisplatin efficacy in human cancer cells. Nutrients 10:1644. https://doi.org/10.3390/nu10111644CrossRefPubMedCentral Heyza JR, Arora S, Zhang H, Conner KL, Lei W, Floyd AM, Deshmukh RR, Sarver J, Trabbic CJ, Erhardt P, Chan TH, Dou QP, Patrick SM (2018) Targeting the DNA repair endonuclease ERCC1–XPF with green tea polyphenol epigallocatechin-3-gallate (EGCG) and its prodrug to enhance cisplatin efficacy in human cancer cells. Nutrients 10:1644. https://​doi.​org/​10.​3390/​nu10111644CrossRefPubMedCentral
9.
Zurück zum Zitat Jordheim LP, Barakat KH, Heinrich-Balard L, Matera EL, Cros-Perrial E, Bouledrak K, El SR, Perez-Pineiro R, Wishart DS, Cohen R, Tuszynski J, Dumontet C (2013) Small molecule inhibitors of ERCC1–XPF protein–protein interaction synergize alkylating agents in cancer cellss. Mol Pharmacol 84:12–24. https://doi.org/10.1124/mol.112.082347CrossRefPubMed Jordheim LP, Barakat KH, Heinrich-Balard L, Matera EL, Cros-Perrial E, Bouledrak K, El SR, Perez-Pineiro R, Wishart DS, Cohen R, Tuszynski J, Dumontet C (2013) Small molecule inhibitors of ERCC1–XPF protein–protein interaction synergize alkylating agents in cancer cellss. Mol Pharmacol 84:12–24. https://​doi.​org/​10.​1124/​mol.​112.​082347CrossRefPubMed
10.
12.
Zurück zum Zitat Hill JM, Speer RJ (1982) Organo-platinum complexes as antitumor agents. (Review). Anticancer Res 2:173–185PubMed Hill JM, Speer RJ (1982) Organo-platinum complexes as antitumor agents. (Review). Anticancer Res 2:173–185PubMed
13.
Zurück zum Zitat Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Annicchiarico-Petruzzelli M, Antonov AV, Arama E, Baehrecke EH, Barlev NA, Bazan NG, Bernassola F, Bertrand MJM, Bianchi K, Blagosklonny MV, Blomgren K, Borner C, Boya P, Brenner C, Campanella M, Candi E, Carmona-Gutierrez D, Cecconi F, Chan FKM, Chandel NS, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Cohen GM, Conrad M, Cubillos-Ruiz JR, Czabotar PE, D’Angiolella V, Dawson TM, Dawson VL, De Laurenzi V, De Maria R, Debatin KM, Deberardinis RJ, Deshmukh M, Di Daniele N, Di Virgilio F, Dixit VM, Dixon SJ, Duckett CS, Dynlacht BD, El-Deiry WS, Elrod JW, Fimia GM, Fulda S, García-Sáez AJ, Garg AD, Garrido C, Gavathiotis E, Golstein P, Gottlieb E, Green DR, Greene LA, Gronemeyer H, Gross A, Hajnoczky G, Hardwick JM, Harris IS, Hengartner MO, Hetz C, Ichijo H, Jäättelä M, Joseph B, Jost PJ, Juin PP, Kaiser WJ, Karin M, Kaufmann T, Kepp O, Kimchi A, Kitsis RN, Klionsky DJ, Knight RA, Kumar S, Lee SW, Lemasters JJ, Levine B, Linkermann A, Lipton SA, Lockshin RA, López-Otín C, Lowe SW, Luedde T, Lugli E, MacFarlane M, Madeo F, Malewicz M, Malorni W, Manic G, Marine JC, Martin SJ, Martinou JC, Medema JP, Mehlen P, Meier P, Melino S, Miao EA, Molkentin JD, Moll UM, Muñoz-Pinedo C, Nagata S, Nuñez G, Oberst A, Oren M, Overholtzer M, Pagano M, Panaretakis T, Pasparakis M, Penninger JM, Pereira DM, Pervaiz S, Peter ME, Piacentini M, Pinton P, Prehn JHM, Puthalakath H, Rabinovich GA, Rehm M, Rizzuto R, Rodrigues CMP, Rubinsztein DC, Rudel T, Ryan KM, Sayan E, Scorrano L, Shao F, Shi Y, Silke J, Simon HU, Sistigu A, Stockwell BR, Strasser A, Szabadkai G, Tait SWG, Tang D, Tavernarakis N, Thorburn A, Tsujimoto Y, Turk B, Vanden Berghe T, Vandenabeele P, Vander Heiden MG, Villunger A, Virgin HW, Vousden KH, Vucic D, Wagner EF, Walczak H, Wallach D, Wang Y, Wells JA, Wood W, Yuan J, Zakeri Z, Zhivotovsky B, Zitvogel L, Melino G, Kroemer G (2018) Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ 25:486–541. https://doi.org/10.1038/s41418-017-0012-4CrossRefPubMedPubMedCentral Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Annicchiarico-Petruzzelli M, Antonov AV, Arama E, Baehrecke EH, Barlev NA, Bazan NG, Bernassola F, Bertrand MJM, Bianchi K, Blagosklonny MV, Blomgren K, Borner C, Boya P, Brenner C, Campanella M, Candi E, Carmona-Gutierrez D, Cecconi F, Chan FKM, Chandel NS, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Cohen GM, Conrad M, Cubillos-Ruiz JR, Czabotar PE, D’Angiolella V, Dawson TM, Dawson VL, De Laurenzi V, De Maria R, Debatin KM, Deberardinis RJ, Deshmukh M, Di Daniele N, Di Virgilio F, Dixit VM, Dixon SJ, Duckett CS, Dynlacht BD, El-Deiry WS, Elrod JW, Fimia GM, Fulda S, García-Sáez AJ, Garg AD, Garrido C, Gavathiotis E, Golstein P, Gottlieb E, Green DR, Greene LA, Gronemeyer H, Gross A, Hajnoczky G, Hardwick JM, Harris IS, Hengartner MO, Hetz C, Ichijo H, Jäättelä M, Joseph B, Jost PJ, Juin PP, Kaiser WJ, Karin M, Kaufmann T, Kepp O, Kimchi A, Kitsis RN, Klionsky DJ, Knight RA, Kumar S, Lee SW, Lemasters JJ, Levine B, Linkermann A, Lipton SA, Lockshin RA, López-Otín C, Lowe SW, Luedde T, Lugli E, MacFarlane M, Madeo F, Malewicz M, Malorni W, Manic G, Marine JC, Martin SJ, Martinou JC, Medema JP, Mehlen P, Meier P, Melino S, Miao EA, Molkentin JD, Moll UM, Muñoz-Pinedo C, Nagata S, Nuñez G, Oberst A, Oren M, Overholtzer M, Pagano M, Panaretakis T, Pasparakis M, Penninger JM, Pereira DM, Pervaiz S, Peter ME, Piacentini M, Pinton P, Prehn JHM, Puthalakath H, Rabinovich GA, Rehm M, Rizzuto R, Rodrigues CMP, Rubinsztein DC, Rudel T, Ryan KM, Sayan E, Scorrano L, Shao F, Shi Y, Silke J, Simon HU, Sistigu A, Stockwell BR, Strasser A, Szabadkai G, Tait SWG, Tang D, Tavernarakis N, Thorburn A, Tsujimoto Y, Turk B, Vanden Berghe T, Vandenabeele P, Vander Heiden MG, Villunger A, Virgin HW, Vousden KH, Vucic D, Wagner EF, Walczak H, Wallach D, Wang Y, Wells JA, Wood W, Yuan J, Zakeri Z, Zhivotovsky B, Zitvogel L, Melino G, Kroemer G (2018) Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ 25:486–541. https://​doi.​org/​10.​1038/​s41418-017-0012-4CrossRefPubMedPubMedCentral
18.
Zurück zum Zitat Volpe A, Racioppi M, D’Agostino D, Cappa E, Filianoti A, Bassi PF (2010) Mitomycin C for the treatment of bladder cancer. Minerva Urol Nefrol 62:133–144PubMed Volpe A, Racioppi M, D’Agostino D, Cappa E, Filianoti A, Bassi PF (2010) Mitomycin C for the treatment of bladder cancer. Minerva Urol Nefrol 62:133–144PubMed
22.
23.
Zurück zum Zitat Thomas AM, Brolih S, McGouran JF, El-Sagheer AH, Ptchelkine D, Jones M, McDonald NQ, McHugh PJ, Brown T (2019) Optimised oligonucleotide substrates to assay XPF-ERCC1 nuclease activity for the discovery of DNA repair inhibitors. Chem Commun 55:11671–11674. https://doi.org/10.1039/c9cc05476fCrossRef Thomas AM, Brolih S, McGouran JF, El-Sagheer AH, Ptchelkine D, Jones M, McDonald NQ, McHugh PJ, Brown T (2019) Optimised oligonucleotide substrates to assay XPF-ERCC1 nuclease activity for the discovery of DNA repair inhibitors. Chem Commun 55:11671–11674. https://​doi.​org/​10.​1039/​c9cc05476fCrossRef
Metadaten
Titel
Enhancing the activity of platinum-based drugs by improved inhibitors of ERCC1–XPF-mediated DNA repair
verfasst von
Gloria Ciniero
Ahmed H. Elmenoufy
Francesco Gentile
Michael Weinfeld
Marco A. Deriu
Frederick G. West
Jack A. Tuszynski
Charles Dumontet
Emeline Cros-Perrial
Lars Petter Jordheim
Publikationsdatum
05.01.2021
Verlag
Springer Berlin Heidelberg
Erschienen in
Cancer Chemotherapy and Pharmacology / Ausgabe 2/2021
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-020-04213-x

Weitere Artikel der Ausgabe 2/2021

Cancer Chemotherapy and Pharmacology 2/2021 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.