Enhancing the activity of platinum-based drugs by improved inhibitors of ERCC1-XPF-mediated DNA repair.
A549 Cells
Antineoplastic Combined Chemotherapy Protocols
/ administration & dosage
Cisplatin
/ administration & dosage
Colonic Neoplasms
/ drug therapy
Computer Simulation
DNA Repair
/ genetics
DNA-Binding Proteins
/ genetics
Drug Synergism
Endonucleases
/ genetics
HCT116 Cells
Humans
Lung Neoplasms
/ drug therapy
Mitomycin
/ administration & dosage
Cancer
Chemical synthesis
DNA repair
Protein–protein interaction
Journal
Cancer chemotherapy and pharmacology
ISSN: 1432-0843
Titre abrégé: Cancer Chemother Pharmacol
Pays: Germany
ID NLM: 7806519
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
08
06
2020
accepted:
10
12
2020
pubmed:
6
1
2021
medline:
24
6
2021
entrez:
5
1
2021
Statut:
ppublish
Résumé
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. 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. 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. 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.
Identifiants
pubmed: 33399940
doi: 10.1007/s00280-020-04213-x
pii: 10.1007/s00280-020-04213-x
doi:
Substances chimiques
DNA-Binding Proteins
0
xeroderma pigmentosum group F protein
0
Mitomycin
50SG953SK6
ERCC1 protein, human
EC 3.1.-
Endonucleases
EC 3.1.-
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
259-267Références
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