Format

Send to

Choose Destination
Clin Cancer Res. 2008 May 15;14(10):3168-76. doi: 10.1158/1078-0432.CCR-07-4362.

Aspirin sensitizes cancer cells to TRAIL-induced apoptosis by reducing survivin levels.

Author information

1
Cell Death Regulation Laboratory, Department of Medicine and Cell and Molecular Biology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

Abstract

PURPOSE:

Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic antibodies targeting its receptors are promising cancer therapies because of their tumor selectivity, many tumors are resistant to TRAIL-based therapies. We examined whether the nonsteroidal anti-inflammatory drug aspirin sensitized cancer cells to TRAIL agonists in vitro and in vivo and investigated the underlying mechanism.

EXPERIMENTAL DESIGN:

The effects of aspirin on sensitivity to TRAIL agonists and expression of apoptosis regulators was determined in human breast cancer cell lines and xenograft tumors. The specific role of survivin depletion in the TRAIL-sensitizing effects of aspirin was determined by silencing survivin.

RESULTS:

Aspirin sensitized human breast cancer cells, but not untransformed human mammary epithelial cells, to TRAIL-induced caspase activation and apoptosis by a cyclooxygenase-2-independent mechanism. Aspirin also sensitized breast cancer cells to apoptosis induced by a human agonistic TRAIL receptor-2 monoclonal antibody (lexatumumab). Aspirin treatment led to G1 cell cycle arrest and a robust reduction in the levels of the antiapoptotic protein survivin by inducing its proteasomal degradation, but did not affect the levels of many other apoptosis regulators. Silencing survivin with small interfering RNAs sensitized breast cancer cells to TRAIL-induced apoptosis, underscoring the functional role of survivin depletion in the TRAIL-sensitizing actions of aspirin. Moreover, aspirin acted synergistically with TRAIL to promote apoptosis and reduce tumor burden in an orthotopic breast cancer xenograft model.

CONCLUSIONS:

Aspirin sensitizes transformed breast epithelial cells to TRAIL-based therapies in vitro and in vivo by a novel mechanism involving survivin depletion. These findings provide the first in vivo evidence for the therapeutic utility of this combination.

PMID:
18483385
DOI:
10.1158/1078-0432.CCR-07-4362
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center