MLN4924 and 2DG combined treatment enhances the efficiency of radiotherapy in breast cancer cells

Abstract

Purpose: Two-deoxy-D-glucose (2DG) causes cytotoxicity in the cancer cells by disrupting the thiol metabolism, and MLN4924 inactivates the SCF E3 ligase and so causes the accumulation of its substrates which trigger apoptosis and hence might enhance the efficiency of radiotherapy and overcame on the radioresistance of the cancer cells. Materials and methods: SKBR3 and MCF-7 breast cancer cells were treated with 500M 2DG and/or MLN4924 (30, 100, 200 and 300nM), and in combination in the presence and absence of 1, 1.5 and 2Gy gamma irradiation. The effects of the treatments - 2DG, MLN4924, irradiation alone and combined - on MCF-7 and SKBR3 cell lines were evaluated by MTT assay, TUNEL assay, cell death detection, Q-PCR for caspase-3 and Bcl-2 expression analysis, and finally clonogenic survival assay.Results: The treatments enhanced the further radio cytotoxicity via inducing the apoptosis cell signaling gene, caspase-3. The 2DG and MLN4924 treatments could act as a radiosensitizer, especially on the SKBR3 cells, and further sensitized the cells with a sensitivity enhancement ratio (SER) of 1.41 and 1.27 in SKBR3 and MCF-7 cells, respectively.Conclusion: The combined chemo-radiotherapy might improve the breast cancer treatment outcome.