Abstract
BackgroundAcquired radioresistance of cancer cells remains a fundamental barrier to attaining the maximal efficacy of radiotherapy for the treatment of breast cancer. Anti-apoptotic proteins, such as Bcl-2 and Bcl-xL, play an important role in the radioresistance of cancer cells. In the present study, we aimed to determine if ABT-737, a BH3-only mimic, could reverse the acquired radioresistance of the breast cancer cell line MDA-MB-231R by targeting Bcl-2 and Bcl-xL.MethodsThe radiosensitivity of MDA-MB-231 and MDA-MB-231R cells was compared using colony formation assays. Reverse-transcription PCR and western blot were performed to detect the expression of Bcl-2 and Bcl-xL in the cancer cell lines. Annexin V flow cytometric analysis and caspase-3 colorimetric assay were used to evaluate apoptosis of the cancer cells. Cell viability was measured using the Cell Counting Kit-8. The animals used in this study were 4 to 6-week-old athymic female BALB/c nu/nu mice.ResultsThe MDA-MB-231R cells were more radioresistant than the MDA-MB-231 cells, and Bcl-2 and Bcl-xL were overexpressed in the MDA-MB-231R cells. While ABT-737 was able to restore the radiosensitivity of the MDA-MB-231R cells in vitro and in vivo experiment, it was not able to enhance the radiosensitivity of the MDA-MB-231 cells. In addition, ABT-737 increased radiation-induced apoptosis in the MDA-MB-231R cells. Bcl-2 and Bcl-xL were down regulated in the MDA-MB-231R cells following treatment with ABT-737.ConclusionsTargeting of the anti-apoptotic proteins Bcl-2 and Bcl-xL with ABT-737 may reverse the acquired radioresistance of MDA-MB-231R cells in vitro and in vivo. These findings suggest an attractive strategy for overcoming the acquired radioresistance of breast cancer cells.
Highlights
Acquired radioresistance of cancer cells remains a fundamental barrier to attaining the maximal efficacy of radiotherapy for the treatment of breast cancer
Bcl-2 and Bcl-xL are overexpressed in MDA-MB-231R cells Because anti-apoptotic proteins could enable the radio resistance of the cancer cells, we investigated whether the expression of Bcl-2 and Bcl-xL, important proteins involved in apoptosis, were altered in the MDA-MB-231R cells
Western blotting showed a significant increase in Bcl-2 and Bcl-xL expression in the MDA-MB-231R cells compared to MDA-MB-231 cells (Figure 2A)
Summary
Acquired radioresistance of cancer cells remains a fundamental barrier to attaining the maximal efficacy of radiotherapy for the treatment of breast cancer. Anti-apoptotic proteins, such as Bcl-2 and Bcl-xL, play an important role in the radioresistance of cancer cells. Radiotherapy plays an important role in the treatment of breast cancer. Programmed cell death, is the mechanism of radiation-induced cancer cell death [6,7]. It is regulated by complex interactions between anti-apoptotic proteins such as Bcl-2, Bcl-xL and Mcl-1, and pro-apoptotic proteins including Bax, Bak, Bad and Bim [8,9]. Down regulation of anti-apoptotic proteins can promote apoptosis and enhance the radiosensitivity of cancer cells [10,11,12,13]. The disruption of anti-apoptotic pathways is a novel target for overcoming radioresistance in breast cancer
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