The Novel, Orally Bioavailable CDK9 Inhibitor Atuveciclib Sensitises Pancreatic Cancer Cells to TRAIL-induced Cell Death.
Apoptosis
/ drug effects
Cell Cycle
/ drug effects
Cell Line, Tumor
Cell Survival
/ drug effects
Cyclin-Dependent Kinase 9
/ antagonists & inhibitors
Dose-Response Relationship, Drug
Drug Synergism
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Pancreatic Neoplasms
/ genetics
Protein Kinase Inhibitors
/ pharmacology
Receptors, TNF-Related Apoptosis-Inducing Ligand
/ metabolism
Sulfonamides
/ pharmacology
TNF-Related Apoptosis-Inducing Ligand
/ pharmacology
Triazines
/ pharmacology
Atuveciclib
CDK9
TRAIL
apoptosis
pancreatic cancer
pancreatic ductal adenocarcinoma
Journal
Anticancer research
ISSN: 1791-7530
Titre abrégé: Anticancer Res
Pays: Greece
ID NLM: 8102988
Informations de publication
Date de publication:
Dec 2021
Dec 2021
Historique:
received:
13
09
2021
revised:
27
09
2021
accepted:
28
09
2021
entrez:
1
12
2021
pubmed:
2
12
2021
medline:
15
12
2021
Statut:
ppublish
Résumé
This study was designed to analyse the effects of the novel, orally bioavailable CDK9-inhibitor Atuveciclib (BAY 1143572) in combination with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) on pancreatic ductal adenocarcinoma (PDAC) cancer cells. To assess the effect of combinatorial use of atuveciclib and TRAIL on pancreatic cancer cells, we used an MTT assay, colony formation assay, flow cytometry, and western blot analysis. Atuveciclib combined with TRAIL significantly reduced the viability of pancreatic cancer cells and their colony formation potential by inducing apoptosis and cell-cycle arrest. Atuveciclib sensitised PDAC cells to TRAIL-induced cell death through the concomitant suppression of cFlip and Mcl-1. A gemcitabine-resistant PDAC cell-line and patient-derived xenograft (PDX) cell lines were also suppressed by this combinatorial approach. This study provides the basis for further preclinical and clinical evaluation of combined treatment with atuveciclib and TRAIL.
Sections du résumé
BACKGROUND/AIM
OBJECTIVE
This study was designed to analyse the effects of the novel, orally bioavailable CDK9-inhibitor Atuveciclib (BAY 1143572) in combination with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) on pancreatic ductal adenocarcinoma (PDAC) cancer cells.
MATERIALS AND METHODS
METHODS
To assess the effect of combinatorial use of atuveciclib and TRAIL on pancreatic cancer cells, we used an MTT assay, colony formation assay, flow cytometry, and western blot analysis.
RESULTS
RESULTS
Atuveciclib combined with TRAIL significantly reduced the viability of pancreatic cancer cells and their colony formation potential by inducing apoptosis and cell-cycle arrest. Atuveciclib sensitised PDAC cells to TRAIL-induced cell death through the concomitant suppression of cFlip and Mcl-1. A gemcitabine-resistant PDAC cell-line and patient-derived xenograft (PDX) cell lines were also suppressed by this combinatorial approach.
CONCLUSION
CONCLUSIONS
This study provides the basis for further preclinical and clinical evaluation of combined treatment with atuveciclib and TRAIL.
Identifiants
pubmed: 34848451
pii: 41/12/5973
doi: 10.21873/anticanres.15416
doi:
Substances chimiques
Protein Kinase Inhibitors
0
Receptors, TNF-Related Apoptosis-Inducing Ligand
0
Sulfonamides
0
TNF-Related Apoptosis-Inducing Ligand
0
Triazines
0
atuveciclib
0
CDK9 protein, human
EC 2.7.11.22
Cyclin-Dependent Kinase 9
EC 2.7.11.22
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
5973-5985Informations de copyright
Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.