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The Novel, Orally Bioavailable CDK9 Inhibitor Atuveciclib Sensitises Pancreatic Cancer Cells to TRAIL-induced Cell Death

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.

 

Comments:

The study you've described is focused on investigating the effects of a novel orally bioavailable CDK9 inhibitor called Atuveciclib (also known as BAY 1143572) in combination with TRAIL (Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand) on pancreatic ductal adenocarcinoma (PDAC) cancer cells. Here's a breakdown of the study:

1. **Background/Aim:**
   - The primary objective of this study is to analyze the impact of combining Atuveciclib and TRAIL on PDAC cancer cells.
   - CDK9 is a protein involved in cell cycle regulation, and inhibiting it can potentially affect cancer cell growth.
   - TRAIL is a protein that can induce apoptosis (cell death) in cancer cells.

2. **Materials and Methods:**
   - The study employed various experimental techniques to assess the effects of the combination treatment:
     - MTT assay: Used to measure cell viability.
     - Colony formation assay: Examined the ability of cancer cells to form colonies, indicating their proliferative potential.
     - Flow cytometry: Likely used to analyze cell cycle distribution and apoptosis.
     - Western blot analysis: To study protein expression changes in treated cells.

3. **Results:**
   - The combination of Atuveciclib and TRAIL had significant effects on pancreatic cancer cells:
     - Reduced cell viability: The treatment decreased the overall survival of cancer cells.
     - Inhibited colony formation: This suggests a reduction in the cancer cells' ability to grow and reproduce.
     - Induced apoptosis: The combination treatment triggered programmed cell death in cancer cells.
     - Caused cell-cycle arrest: It likely disrupted the normal progression of the cell cycle in cancer cells.
     - Suppressed cFlip and Mcl-1: These are proteins that may promote cell survival. The treatment reduced their expression, making cancer cells more susceptible to TRAIL-induced cell death.

4. **Conclusion:**
   - The study's findings support the potential therapeutic efficacy of combining Atuveciclib and TRAIL for treating PDAC:
     - The combination treatment was effective in reducing cancer cell viability and growth.
     - It induced apoptosis and cell-cycle arrest, both of which are desirable outcomes in cancer therapy.
     - Importantly, even gemcitabine-resistant PDAC cells and patient-derived xenograft (PDX) cell lines responded positively to this combination therapy.
   - The results suggest that this approach warrants further investigation in both preclinical and clinical settings, indicating a promising avenue for future cancer treatment research.

Overall, this study provides a strong foundation for exploring the use of Atuveciclib in combination with TRAIL as a potential treatment strategy for pancreatic ductal adenocarcinoma, especially in cases where traditional therapies may be less effective. Further research and clinical trials will be needed to validate and refine this approach.

Related Products

Cat.No. Product Name Information
S8727 Atuveciclib (BAY-1143572) Atuveciclib (BAY-1143572) is a potent and highly selective PTEFb/CDK9 inhibitor with IC50 values of 13 nM for CDK9/CycT and the ratio of IC50 values for CDK2/CDK9 is about 100. Outside the CDK family, It inhibits GSK3 kinase with IC50 values of 45 nM and 87 nM for GSK3α and GSK3β respectively.

Related Targets

CDK