Ailanthone synergizes with PARP1 inhibitor in tumour growth inhibition through crosstalk of DNA repair pathways in gastric cancer.
PARP1
ailanthone
gastric cancer
synergizes
tumour growth inhibition
Journal
Journal of cellular and molecular medicine
ISSN: 1582-4934
Titre abrégé: J Cell Mol Med
Pays: England
ID NLM: 101083777
Informations de publication
Date de publication:
27 Nov 2023
27 Nov 2023
Historique:
revised:
25
10
2023
received:
30
08
2023
accepted:
27
10
2023
medline:
27
11
2023
pubmed:
27
11
2023
entrez:
27
11
2023
Statut:
aheadofprint
Résumé
In our previous research, we proved that ailanthone (AIL) inhibits the growth of gastric cancer (GC) cells and causes apoptosis by inhibiting P23. However, we still find some GC organoids are insensitive to AIL. We have done some sequencing analysis and found that the insensitive strains are highly expressed in PARP1. In this study, we investigated whether AIL can enhance the anti-tumour effect of PARPi in GC. CCK8 and spheroid colony formation assay were used to measure anti-tumour effects. SynergyFinder software was used to calculate the synergy score of the drug combination and flow cytometry was used to detect apoptosis. Western blot, IHC, IF tests were used to measure protein expression. Finally, nude mouse xenograft models were used to verify the in vitro mechanisms. High expression of PARP1 was found to be the cause of drug insensitivity. When AIL is paired with a PARP1 inhibitor, olaparib (OLP), drug sensitivity improves. We discovered that this combination functions by blocking off HSP90-BRCA1 interaction and inhibiting the activity of PARP1, thus in turn inhibiting the homologous recombination deficiency and base excision repair pathway to finally achieve synthetic lethality through increased sensitivity. Moreover, P23 can regulate BRCA1 in GC in vitro. This study proves that the inhibitory effect of AIL on BRCA1 allowed even cancer cells with normal BRCA1 function to be sensitive to PARP inhibitors when it is simultaneously administered with OLP. The results greatly expanded the scope of the application of PARPi.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : The Guangxi Young and Middle-aged Teachers Basic Ability Promoting Project
ID : 2022KY0105
Organisme : Guangxi Postdoctoral Special Fundings
ID : 202110
Organisme : Ability Promoting Project
ID : 2022KY0105
Organisme : The Open Project of Guangxi Key Laboratory of Regenerative Medicine
ID : 201904
Organisme : Guangxi Postdoctoral Special Funding
ID : 202110
Organisme : Joint Project on Regional High-Incidence Diseases Research of Guangxi Natural Science Foundation
ID : 2022JJA141119
Informations de copyright
© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
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