Inhibition of c-FLIP alongside TRAIL treatment suppresses prostate cancer stem cell activity

Daniel J Turnham1,2, Rhiannon French3, Fiona M Frame4

  • 1European Cancer Stem Cell Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cathays, Cardiff, CF24 4HQ, UK. daniel.turnham@uwe.ac.uk.

PubMed
Abstract

Insights

Inhibiting Cellular FLICE-like Inhibitory Protein (cFLIP) with OH14 and TRAIL or docetaxel shows promise for treating prostate cancer. This combination therapy effectively reduces cancer cell viability and stem cell activity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Prostate cancer remains a significant cause of male cancer mortality globally.
  • Cellular FLICE-like Inhibitory Protein (cFLIP) overexpression is noted in prostate cancer.
  • Targeting cFLIP with TRAIL can induce apoptosis and reduce cancer stem cell (CSC) activity in various cancers, but its role in prostate cancer requires further investigation.

Purpose of the Study:

  • To investigate the efficacy of inhibiting cFLIP in combination with TRAIL or docetaxel in prostate cancer.
  • To evaluate the impact on cancer cell viability, colony formation, and CSC activity.

Main Methods:

  • Prostate cancer cell lines and patient-derived xenografts (PDX) were treated with a cFLIP inhibitor (OH14) and/or TRAIL.
  • Docetaxel resistance models were utilized, with treatments including OH14 +/- docetaxel.
  • In vitro and in vivo assays assessed viability, colony formation, and CSC activity.

Main Results:

  • Combined OH14 and TRAIL treatment significantly enhanced apoptosis and reduced viability and CSC activity in prostate cancer cells.
  • OH14 sensitized prostate cancer cells to docetaxel, both in vitro and in vivo.
  • Patient-derived xenograft (PDX) models demonstrated the efficacy of combination therapies.

Conclusions:

  • Inhibition of cFLIP, in combination with TRAIL or docetaxel, presents a potential novel therapeutic strategy for prostate cancer.
  • This approach may offer more potent and durable therapeutic benefits for patients.
  • Targeting cFLIP could overcome docetaxel resistance in prostate cancer.

Related Concept Videos

Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Cancer Stem Cells and Tumor Maintenance02:40

Cancer Stem Cells and Tumor Maintenance

Early diagnosis and treatment can often cure cancer. However, even with treatment, residual cells called cancer stem cells (CSC) might remain, often causing tumor recurrence. These cancer stem cells possess the potential for self-renewal and multi-lineage differentiation and are often responsible for the therapeutic resistance displayed in most cancers.
Cancer stem cells are thought to originate from tissue-specific normal stem cells or progenitor cells. The normal stem cells usually reside in...
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against specific...
Inhibition of CDK Activity02:34

Inhibition of CDK Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Cancer Stem Cells and Tumor Maintenance02:40

Cancer Stem Cells and Tumor Maintenance

Early diagnosis and treatment can often cure cancer. However, even with treatment, residual cells called cancer stem cells (CSC) might remain, often causing tumor recurrence. These cancer stem cells possess the potential for self-renewal and multi-lineage differentiation and are often responsible for the therapeutic resistance displayed in most cancers.
Cancer stem cells are thought to originate from tissue-specific normal stem cells or progenitor cells. The normal stem cells usually reside in...