The continued reliance of CRPC on AR signaling offers opportunities to develop

CCI 779 INNO-406 SRC 阻害剤 blocks both G2/M and G1/S cell cycle progression and decreases cell proliferation in CRPC and ADPC cells As UBE2C plays an essential role in promoting G2/M phase cell cycle progression in prostate cancer cells and CCI 779 inhibited UBE2C expression, we next examined the effect of CCI 779 on G2/M phase cell cycle progression. abl, C4 2B and LNCaP cells were synchronized to G2/M phase by using a thymidine nocodazole block and then released for 1 2 hours. As shown in Fig. 2A, while treatment of cells with CCI 779 had no effect on G2/M synchronization, CCI 779 treatment led to an increase in the G2/M phase and a decrease in the G1 phase after releasing from G2/M synchronization, suggesting that CCI 779 markedly delayed G2/M to G1 transition in all three cell lines.<br><br> Consistent with the functional role of CCI 779 in decreasing CCND1 protein expression level and a recent study demonstrating that CCI 779 arrests prostate and breast cancer cells in G1/S phase, CCI 779 blocked unsynchronized abl, C4 2B and LNCaP cells in G1/S phase. The inhibition of CCI 779 on cell cycle G2/M and G1/S progression Lapatinib 388082-77-7 was correlated with a significantly decreased cell proliferation of abl, C4 2B and LNCaP. To further delineate the role of UBE2C in CCI 779 mediated CRPC cell proliferation inhibition, the effects of CCI 779 on cell proliferation of UBE2C silenced or control silenced abl and C4 2B cells were examined. The inhibitory effect of CCI 779 on abl cell proliferation was markedly decreased in UBE2C silenced versus control silenced abl cells, suggesting that UBE2C silencing mediated abl cell growth inhibition significantly contributes to growth inhibitory effect of CCI 779 on abl.<br><br> By contrast, as UBE2C silencing only slightly decreased C4 2B cell proliferation, CCI 779 mediated inhibition of C4 2B cell proliferation was presumably mostly due to CCI 779 induced decreased expression of CCND1 rather than UBE2C in C4 2B cells. supplier Lonafarnib CCI 779 inhibits in vivo growth of abl xenograft through downregulation of UBE2C and CCND1 We further extended our studies to an in vivo xenograft model to validate the significance of our in vitro findings. Approximately two weeks after the inoculation of abl cells, mice were treated with CCI 779 for 4 consecutive days weekly for 4 weeks. Mice generally tolerated CCI 779 without showing any apparent toxicity throughout the experiment.<br><br> No significant difference in body weight was observed between groups after the four weeks period. Remarkably, the tumor growth was inhibited by CCI 779 even after one week of treatment. By the end of the study, the tumor volume dramatically decreased from 234 33mm3 in control group to 57 4 mm3 in CCI 779 treated group. In addition, there was no measurable tumor in 4 out of 10 CCI 779 treated mice. Tumor weight measurement further supported our findings, as the average value was 78. 6 15. 5 mg for control group as compared with 13. 5 2. 5 mg for CCI 779 group. More importantly, western blot analysis confirmed that both UBE2C and CCND1 protein levels were significantly decreased in tumor tissues following treatment with CCI 779. These data suggest that CCI 779 significantly decreases CRPC cell in vivo growth through inhibition of UBE2C and CCND1. Similar effect of CCI 779 on CRPC cell growth and protein expression of CCND1 and UBE2C was observed in castrated mice.