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Cell cycle-arrested tumor cells exhibit increased sensitivity towards TRAIL-induced apoptosis

H Ehrhardt1, F Wachter, M Grunert

  • 1Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.

Cell Death & Disease
|June 8, 2013
PubMed

Insights

Tumor cells arrested in the cell cycle are more susceptible to TNF-related apoptosis-inducing ligand (TRAIL) therapy. This finding suggests TRAIL could be effective against minimal residual disease and static tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Resting tumor cells exhibit resistance to conventional anticancer therapies.
  • TNF-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent currently in clinical trials.
  • Previous research indicated TRAIL's efficacy against leukemia stem cell surrogates.

Purpose of the Study:

  • To investigate the efficacy of TRAIL against tumor cells arrested at various stages of the cell cycle.
  • To determine if cell cycle arrest enhances TRAIL-induced apoptosis.
  • To assess the clinical translatability of TRAIL in pediatric acute lymphoblastic leukemia.

Main Methods:

  • Tumor cell lines and xenografted tumors were induced into cell cycle arrest (G0, G1, or G2) using cytotoxic drugs, specific inhibitors, or RNA interference targeting cyclin B and E.
  • TRAIL-induced apoptosis was measured in arrested versus non-arrested cells.
  • The effect of caffeine on TRAIL sensitivity was evaluated.
  • TRAIL-induced apoptosis was assessed in pediatric acute lymphoblastic leukemia cells with reduced cyclin B or E expression.

Main Results:

  • Biochemical or molecular cell cycle arrest at any phase (G0, G1, G2) significantly increased TRAIL-induced apoptosis.
  • Disabling cell cycle arrest with caffeine reduced TRAIL's antitumor activity.
  • Pediatric acute lymphoblastic leukemia cells with reduced cyclin B or E (cell cycle arrest) showed enhanced TRAIL-induced apoptosis.

Conclusions:

  • Unlike conventional cytotoxic drugs, TRAIL demonstrates enhanced antitumor activity against cell cycle-arrested tumor cells.
  • TRAIL holds potential as a therapeutic agent for static-tumor diseases, including minimal residual disease.
  • Targeting cell cycle-arrested cells with TRAIL represents a novel therapeutic strategy in oncology.

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