Anticancer research · 2021
The Novel, Orally Bioavailable CDK9 Inhibitor Atuveciclib Sensitises Pancreatic Cancer Cells to TRAIL-induced Cell Death.
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Ruff Jan-Philipp, Kretz Anna-Laura, Kornmann Marko, Henne-Bruns Doris, Lemke Johannes, Traub Benno
Аннотация
BACKGROUND/AIM: 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: 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: 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: This study provides the basis for further preclinical and clinical evaluation of combined treatment with atuveciclib and TRAIL.
MATERIALS AND 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: 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: This study provides the basis for further preclinical and clinical evaluation of combined treatment with atuveciclib and TRAIL.
Предметные рубрики MeSH
ApoptosisCell CycleCell Line, TumorCell SurvivalCyclin-Dependent Kinase 9Dose-Response Relationship, DrugDrug SynergismGene Expression Regulation, NeoplasticHumansPancreatic NeoplasmsProtein Kinase InhibitorsReceptors, TNF-Related Apoptosis-Inducing LigandSulfonamidesTNF-Related Apoptosis-Inducing LigandTriazines