Synergistic antitumor effect of TRAIL and adriamycin on the human breast cancer cell line MCF-7

D.D Cui,Y Huang,L.L Ji,M Qiu,S.C Chen,C Yi,S.H Mao

doi:10.1590/s0100-879x2009000900013

Abstract

The aim of the present study was to determine the effect of the combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and adriamycin (ADM) on the human breast cancer cell line MCF-7 and to identify potential mechanisms of apoptosis. Cell viability was analyzed by the MTT assay and the synergistic effect was assessed by the Webb coefficient. Apoptosis was quantified using the annexin V-FITC and propidium iodide staining flow cytometry. The mRNA expression of TRAIL receptors was measured by RT-PCR. Changes in the quantities of Bax and caspase-9 proteins were determined by Western blot. MCF-7 cells were relatively resistant to TRAIL (IC50 >10 microg/mL), while MCF-7 cells were sensitive to ADM (IC50 <10 microg/mL). A subtoxic concentration of ADM (0.5 microg/mL) combined with 0.1, 1, or 10 microg/mL TRAIL had a synergistic cytotoxic effect on MCF-7 cells, which was more marked with the combination of TRAIL (0.1 microg/mL) and ADM (0.5 microg/mL). In addition, the combined treatment with TRAIL and ADM significantly increased cell apoptosis from 9.8% (TRAIL) or 17% (ADM) to 38.7%, resulting in a synergistic apoptotic effect, which is proposed to be mediated by up-regulation of DR4 and DR5 mRNA expression and increased expression of Bax and caspase-9 proteins. These results suggest that the combination of TRAIL and ADM might be a promising therapy for breast cancer.

Highlights

Worldwide, breast cancer is the most common form of malignancy in women, with high incidence and mortality rates [1]
IC50 was 100 μg/mL (>10 μg/mL), suggesting that MCF-7 cells were relatively resistant to Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (Figure 1A)
The data showed that human breast cancer MCF-7 cells were relatively resistant to TRAIL, but sensitive to ADM

Summary

Introduction

Breast cancer is the most common form of malignancy in women, with high incidence and mortality rates [1]. Adriamycin (ADM) is among the most effective antitumor drugs used for the management of breast cancer. Its clinical utility is limited by its toxic effects such as myelosuppression, nausea, vomiting, and cardiotoxicity [2]. Novel treatment strategies are urgently needed to improve the clinical management of breast cancer. TRAIL can bind to 5 different receptors: TRAIL-R1 (death receptor 4, DR4), TRAIL-R2 (DR5), TRAIL-R3 (decoy receptor, DcR1), TRAILR4 (DcR2), and osteoprotegerin (OPG). DR4 and DR5 are the death receptors that signal apoptosis, whereas DcR1, DcR2 and OPG are considered antagonistic because they are unable to induce such signaling due to the lack of an intracellular death domain or because they are secreted molecules [4]

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