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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
Summary
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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