Anai et al. demonstrated that down regulation of Bcl-2 could induce radiation sensitivity

in prostate cancer cells [11]. The expression levels of the anti-apoptotic proteins are also correlated with the outcome of patients who received radiotherapy. Yang et al. [25] reported that Bcl-2 expression is associated with an increased risk of the local recurrence in patients with early breast cancer that received breast conservative surgery and radiotherapy. AT-101, a small molecule inhibitor of the Bcl-2 family members, enhanced the radiation-induced apoptosis BKM120 cost of human leukemia cells [26]. We proposed that targeting the overexpression of Bcl-2 and Bcl-xL may be an effective way to overcome the acquired radioresistance of cancer cells. In this study, it was observed that following treatment with 1 μM ABT-737 for 24 hours, the colony formation ability of MDA-MB-231R cells decreased greatly and the radiation-induced apoptosis increased. These data suggested that ABT-737 could reverse the acquired radioresistance

of MDA-MB-231R cells by increasing radiation-induced apoptosis. In vivo, the growth tumors ATR inhibitor in the ABT-737 plus radiation group were reduced compared with the DMSO plus radiation group. However, in contrast to the results obtained with the MDA-MB-231R cells, ABT-737 did not enhance the radiosensitivity of the MDA-MB-231 cells. This could be attributed to the down regulation of Bcl-2 and Bcl-xL expression observed in MDA-MB-231R cells, but not in MDA-MB-231 cells following ABT-737 treatment (Figure 6A and B). The expression levels of Bcl-xL and Bcl-2 in the MDA-MB-231 cells were very low, and treating them with ABT-737 did not down regulate their expression. Although treatment with ABT-737 did not enhance the radiosensitivity of the MDA-MD-231 cells, it reversed

the acquired radioresistance of the MDA-MD-231R cells, making them more likely to be killed by radiation treatment. Eliminating these radioresistant cancer cells is perhaps the most effective method for decreasing the recurrence of cancer following radiotherapy. This is the Chlormezanone first study to show that ABT-737 down regulated the expression of Bcl-2 and Bcl-xL in cancer cells in a KU-57788 time-dependent manner. ABT-737, a rationally designed small molecule binds with high affinity to Bcl-2 and Bcl-xL, thereby antagonizing their anti-apoptotic functions and inducing apoptosis in many types of cancer cell. ABT-737 binds to the multi-domain, anti-apoptotic Bcl-2 family member proteins to prevent them from sequestering the pro-apoptotic BH3-only proteins. In the present study, we found that ABT-737 down regulated the expression of Bcl-2 and Bcl-xL in MDA-MB-231R cells in a time-dependent manner. Similar results were obtained using SK-BR-3 and MCF-7 cells (data not shown). The down regulation of those anti-apoptotic proteins by ABT-737 may at least partly explain its ability to reverse the acquired radioresistance of the MDA-MB-231R cells.