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Histone Deacetylase Inhibitors Sensitize TRAIL-Induced Apoptosis in Colon Cancer Cells

Baojie Zhang1, Bin Liu2, Deng Chen3

  • 1Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. b.z.zhang@rug.nl.

Cancers
|May 15, 2019
PubMed

Insights

Targeted histone deacetylase inhibitors (HDACi) combined with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) variants effectively overcome TRAIL resistance in colon cancer. This combination therapy shows promise for treating resistant colon cancers, including in 3D models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential anti-cancer therapeutic but faces resistance in many cancers.
  • Broad-spectrum histone deacetylase inhibitors (HDACi) show toxicity, limiting clinical application.
  • Class I histone deacetylases (HDACs) are overexpressed in colon tumors, suggesting targeted inhibition as a strategy.

Purpose of the Study:

  • To investigate the efficacy of combining specific class I HDAC inhibitors with TRAIL variants to overcome TRAIL resistance in colon cancer cells.
  • To explore the role of specific HDACs (HDAC1, 2, 3, 8) in TRAIL-induced apoptosis.
  • To evaluate the therapeutic potential of this combination in 3D tumor spheroid models.

Main Methods:

  • Treatment of TRAIL-resistant colon cancer cell lines (DLD-1, WiDr) with specific class I HDAC inhibitors (Entinostat, RGFP966, PCI34051) and TRAIL variants (rhTRAIL 4C7, DHER).
  • Assessment of apoptosis induction via TRAIL-mediated pathways.
  • Gene silencing (knockdown) of HDAC1, 2, and 3 to confirm their roles.
  • Analysis of death receptor (DR4, DR5) expression.
  • Evaluation in 3D tumor spheroid models.

Main Results:

  • Entinostat, RGFP966, or PCI34051 significantly enhanced TRAIL-induced apoptosis in WiDr and DLD-1 cells.
  • HDAC1, 2, or 3 knockdown increased early apoptotic cells upon TRAIL variant treatment.
  • RGFP966 and PCI34051 modulated DR4 and DR5 expression differently in DLD-1 and WiDr cells.
  • Combined treatment of RGFP966 with TRAIL variants increased apoptosis in 3D tumor spheroid models.

Conclusions:

  • Specific class I HDAC inhibitors (RGFP966, PCI34051) combined with TRAIL variants represent a novel and effective strategy against TRAIL-resistant colon cancer.
  • Targeting HDAC3 or HDAC8, in particular, shows promise for enhancing TRAIL therapy.
  • This combination therapy demonstrates efficacy in preclinical 3D models, warranting further investigation.
Keywords:
DLD-1HDACPCI34051RGFP966TRAILWiDrdeath receptorspheroid

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