To confirm this hypothesis, PANC 1 cells were treated with radiation in the absence or presence of AZD8055, the results disclosed that all of the doses of AZD8055 combined with radiation showed a synergetic in Dorsomorphin 1219168-18-9 hibition of cell growth. As shown in Figure 5B, radiation or AZD8055 single treatment caused less than 40% cell growth inhibition, whereas the combination caused more than 80%. Colony formation assay also showed that almost all the PANC 1 cells were eliminated by the combination treatment compared to radiation or AZD8055 treated alone. The similar data were achieved with the other two pancreatic cancer cell lines. Altogether, our data suggest that blockade of mTOR signal pathway by AZD8055 could reverse radioresistance and sensitize pancreatic cancer cells to ionizing radiation.

AZD8055 enhances radiation induced cell cycle disruption and cell apoptosis To evaluate whether AZD8055 combined with radiation affects cell cycle distribution, PANC 1 cells were treated with indicated doses of radiation and Inhibitors,Modulators,Libraries or AZD8055 as de scribed previously. We found that AZD8055 or radiation alone caused a slight accumulation of cells Inhibitors,Modulators,Libraries in G0 G1 phases and a mild reduction in S phase compared with con trol cells, whereas a more extensive cell cycle pertur bation was caused by their combined treatment, with an accumulation of cells in G0 G1 phase, and a sig nificant reduction in S phase. Then Annexin V assay was employed to test whether the combination treatment was accompanied with in creased programmed cell death. As shown in Figure 6B, Radiation or AZD8055 alone merely induced a small number of cells apoptosis by 18.

4% or 11. 7% even at 5 Gy or 500 nM. Intriguingly, AZD8055 combined with radiation synergistically induced significant cell Inhibitors,Modulators,Libraries apop tosis by 48. 2%. Our findings indicate that AZD8055 en hanced ionizing radiation induced cell apoptotic and cell cycle arrest. Suppression of mTOR activation by AZD8055 enhances antitumor efficacy of radiation in pancreatic cancer xenografts Our in vitro studies have proved the principle that radi ation combined with AZD8055 could synergistically in hibit cell proliferation and induce Inhibitors,Modulators,Libraries apoptosis. To evaluate these effects in vivo, mice bearing subcutaneous PANC 1 xenografts were randomized and treated for three weeks as described in Materials and methods.

As indicated in Figure 7A and B, in mice that received fractionated radi ation alone, tumors grew slowly during the early two weeks, then the growth rate resumed similar to the control group, meanwhile in association with high level Inhibitors,Modulators,Libraries of p mTOR in tumor tissues. Interestingly, more coopera tive antitumor effect was observed when AZD8055 was used in Ganetespib combination with fractionated radiation, with a sig nificant reduction of the volumes of the xenografts at the end of treatment in all of the mice as compared with con trol and radiation alone group.