Irradiation specifically sensitises solid tumour cell lines to TRAIL mediated apoptosis

Patrizia Marini,Heidrun Faltin,Angelika Schmid,Claus Belka,Wilfried Budach,Verena Jendrossek,Peter T Daniel

doi:10.1186/1471-2407-5-5

Abstract

BackgroundTRAIL (tumor necrosis factor related apoptosis inducing ligand) is an apoptosis inducing ligand with high specificity for malignant cell systems. Combined treatment modalities using TRAIL and cytotoxic drugs revealed highly additive effects in different tumour cell lines. Little is known about the efficacy and underlying mechanistic effects of a combined therapy using TRAIL and ionising radiation in solid tumour cell systems. Additionally, little is known about the effect of TRAIL combined with radiation on normal tissues.MethodsTumour cell systems derived from breast- (MDA MB231), lung- (NCI H460) colorectal- (Colo 205, HCT-15) and head and neck cancer (FaDu, SCC-4) were treated with a combination of TRAIL and irradiation using two different time schedules. Normal tissue cultures from breast, prostate, renal and bronchial epithelia, small muscle cells, endothelial cells, hepatocytes and fibroblasts were tested accordingly. Apoptosis was determined by fluorescence microscopy and western blot determination of PARP processing. Upregulation of death receptors was quantified by flow cytometry.ResultsThe combined treatment of TRAIL with irradiation strongly increased apoptosis induction in all treated tumour cell lines compared to treatment with TRAIL or irradiation alone. The synergistic effect was most prominent after sequential application of TRAIL after irradiation. Upregulation of TRAIL receptor DR5 after irradiation was observed in four of six tumour cell lines but did not correlate to tumour cell sensitisation to TRAIL. TRAIL did not show toxicity in normal tissue cell systems. In addition, pre-irradiation did not sensitise all nine tested human normal tissue cell cultures to TRAIL.ConclusionsBased on the in vitro data, TRAIL represents a very promising candidate for combination with radiotherapy. Sequential application of ionising radiation followed by TRAIL is associated with an synergistic induction of cell death in a large panel of solid tumour cell lines. However, TRAIL receptor upregulation may not be the sole mechanism by which sensitation to TRAIL after irradiation is induced.

Highlights

tumor necrosis factor (TNF)-related apoptosis inducing ligand. HMEC (TRAIL) is an apoptosis inducing ligand with high specificity for malignant cell systems
It was shown that TRAIL induces tumour cell apoptosis and tumour regression in nude mice, even when applied as single agent [6,7]
Subsequentially it was shown that the biochemical preparation of TRAIL rather than TRAIL itself was responsible for the observed toxic effect on hepatocytes [10]

Summary

Introduction

TRAIL (tumor necrosis factor related apoptosis inducing ligand) is an apoptosis inducing ligand with high specificity for malignant cell systems. Little is known about the efficacy and underlying mechanistic effects of a combined therapy using TRAIL and ionising radiation in solid tumour cell systems. TRAIL (Tumour necrosis factor related apoptosis inducing ligand) is one of the most promising anti-cancer agent being currently under investigation (for review see [1,2,3,4,5]). One possible explanation for the tumour specifity of TRAIL could lie in its potential role as a mediator of tumour immune surveillance in vivo. In this regard it has been shown that mice lacking TRAIL display a significantly reduced capacity to eliminate syngenic tumour cells in the liver [12,13]

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