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Establishing Cell Lines Overexpressing DR3 to Assess the Apoptotic Response to Anti-mitotic Therapeutics
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Establishing Cell Lines Overexpressing DR3 to Assess the Apoptotic Response to Anti-mitotic Therapeutics

Published on: January 11, 2019

Designed tumor necrosis factor-related apoptosis-inducing ligand variants initiating apoptosis exclusively via the

Almer M van der Sloot1, Vicente Tur, Eva Szegezdi

  • 1Department of Pharmaceutical Biology, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.

Proceedings of the National Academy of Sciences of the United States of America
|May 30, 2006
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) variants were engineered to specifically target DR5 receptors. This breakthrough enables selective cancer cell apoptosis induction, even in TRAIL-insensitive tumors, paving the way for novel anticancer therapies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells via DR4 and DR5 receptors.
  • TRAIL also binds to decoy receptors, limiting its therapeutic efficacy.
  • Targeting DR5 offers a strategy for tumor-selective cancer therapies.

Purpose of the Study:

  • To engineer DR5-selective TRAIL variants using computational design.
  • To evaluate the efficacy of these variants in inducing apoptosis in cancer cell lines.

Main Methods:

  • Utilized the FOLD-X algorithm for automatic design of TRAIL variants.
  • Tested engineered TRAIL variants on DR4- and DR5-responsive cancer cell lines.
  • Assessed apoptosis induction in wild-type TRAIL-insensitive ovarian cancer cells.

Main Results:

  • Successfully generated DR5-selective TRAIL variants.
  • Variants showed increased biological activity in DR5-responsive cells, sparing DR4-responsive cells.
  • Induced apoptosis in TRAIL-insensitive ovarian cancer cells without cross-linking or membrane-bound TRAIL.

Conclusions:

  • DR5-selective TRAIL variants represent a promising approach for targeted cancer therapy.
  • These variants overcome resistance mechanisms and enhance apoptosis induction.
  • Apoptosis induction via DR5 does not necessitate antibody-mediated cross-linking or membrane-bound TRAIL.

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