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Bortezomib and TRAIL: a perfect match for apoptotic elimination of tumour cells?

L H A M de Wilt1, J Kroon, G Jansen

  • 1Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.

Critical Reviews in Oncology/Hematology
|September 5, 2012
PubMed

Insights

Bortezomib enhances cancer cell death induced by TRAIL by increasing TRAIL receptors and promoting apoptosis. Preclinical studies show promise, but clinical efficacy needs further demonstration.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine that selectively induces apoptosis in tumor cells.
  • TRAIL receptor agonists are being explored as novel anticancer agents.
  • Bortezomib, a proteasome inhibitor, is a potent sensitizer for TRAIL-based therapies.

Purpose of the Study:

  • To review the mechanisms by which bortezomib enhances TRAIL-induced apoptosis.
  • To discuss preclinical models evaluating the bortezomib-TRAIL combination.
  • To identify potential hurdles for clinical application.

Main Methods:

  • Review of existing literature on bortezomib and TRAIL.
  • Analysis of molecular mechanisms of TRAIL sensitization.
  • Discussion of preclinical data from various tumor models.

Main Results:

  • Bortezomib increases TRAIL receptor expression and enhances caspase-8 activation.
  • Bortezomib reduces levels of cFLIP, Bcl-2 family proteins, and inhibitor of apoptosis proteins (IAPs).
  • Bortezomib suppresses pro-survival signals like NF-κB and Akt.

Conclusions:

  • Bortezomib-TRAIL combination demonstrates a strong preclinical rationale for cancer therapy.
  • Preclinical results are promising across various tumor models, including primary cells and in vivo studies.
  • Clinical efficacy of the bortezomib-TRAIL combination requires further investigation and validation.

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