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Updated: Oct 17, 2026

Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
09:19

Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo

Published on: February 6, 2015

Molecular determinants of response to TRAIL in killing of normal and cancer cells

K Kim1, M J Fisher, S Q Xu

  • 1Howard Hughes Medical Institute, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|February 26, 2000
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) effectively targets cancer cells. TRAIL resistance is linked to low DR4 or high FLIP expression, but can be overcome with doxorubicin.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Apoptosis

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cancer cell death but not normal cell death, showing potential as an antineoplastic agent.
  • TRAIL interacts with proapoptotic death receptors (DR4, KILLER/DR5) and decoy receptors (TRID, TRUNDD).

Purpose of the Study:

  • To identify mechanisms of TRAIL resistance in cancer cell lines.
  • To explore strategies for overcoming TRAIL resistance.

Main Methods:

  • Assessed TRAIL sensitivity in cancer cell lines.
  • Quantified expression levels of DR4, FLIP, KILLER/DR5, TRID, and TRUNDD.
  • Investigated the impact of doxorubicin in combination with TRAIL on TRAIL-resistant cells.

Main Results:

  • TRAIL-resistant cell lines exhibited low/absent DR4 expression or high FLIP expression.
  • A DR4 polymorphism (K441R) was identified in some TRAIL-resistant lines, inhibiting DR4-mediated killing.
  • Doxorubicin sensitized TRAIL-resistant cells to TRAIL-induced apoptosis by promoting caspase activation.

Conclusions:

  • DR4 expression levels, FLIP expression, and the DR4 K441R polymorphism are potential predictors of TRAIL sensitivity.
  • Combining TRAIL with doxorubicin may be an effective strategy to treat TRAIL-resistant tumors.

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