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The long and winding road to cancer treatment: the TRAIL system

Carmen Palacios, Rosario Yerbes, Tania Sanchez-Perez

  • 1Cell Signalling Department, Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas, Avenida Americo Vespucio s/n, 41092 Sevilla, Spain. abelardo.lopez@cabimer.es.

Current Pharmaceutical Design
|August 16, 2013
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promise for cancer therapy by selectively inducing apoptosis in tumor cells. Clinical trials of TRAIL and its receptor agonists are ongoing, despite some adverse effects.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Activation of tumor necrosis factor (TNF) receptor superfamily death receptors is a therapeutic strategy for cancer. TNF-alpha and CD95/Fas ligand (FasL) have toxic effects on normal tissues, limiting clinical use. TNF-related apoptosis-inducing ligand (TRAIL/APO-2L) selectively induces apoptosis in tumor cells and suppresses tumor xenograft growth.
  • Recombinant TRAIL and agonistic TRAIL receptor antibodies show minimal cytotoxicity in preclinical models. Adverse effects of some TRAIL preparations exist, but TRAIL receptor activation remains a promising cancer therapy approach.

Purpose of the Study:

  • To review current knowledge on proapoptotic TRAIL signaling pathways.
  • To explore the role of intracellular survival pathways in TRAIL resistance and non-apoptotic signaling activation.
  • To discuss the involvement of the TRAIL system in tumorigenesis and summarize clinical trial outcomes of TRAIL-based therapies.

Main Methods:

  • Literature review of studies on TRAIL signaling, resistance mechanisms, and clinical trials.
  • Analysis of preclinical data on TRAIL-induced apoptosis and cytotoxicity.
  • Synthesis of information on TRAIL's role in cancer development and therapeutic efficacy.

Main Results:

  • TRAIL selectively induces apoptosis in many cancer cell lines and suppresses tumor xenograft growth in vivo.
  • Recombinant TRAIL and agonistic TRAIL receptor antibodies demonstrate low cytotoxicity in normal tissues.
  • Clinical trials of TRAIL and its receptor agonists, as monotherapy or in combination, are being evaluated for cancer treatment.

Conclusions:

  • Activation of proapoptotic TRAIL receptors is a promising strategy for cancer therapy.
  • Understanding TRAIL resistance mechanisms and non-apoptotic signaling is crucial for optimizing TRAIL-based treatments.
  • Ongoing clinical trials will further define the therapeutic potential of TRAIL and its agonists in oncology.

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