D cross talk between AR and other signaling pathways k Nnte a dramatically positive impact on the strategies for the treatment of prostate cancer. Increasing evidence suggests that regulate key factors of Flavopiridol Alvocidib the PI3K/Akt/mTOR path directly the expression and transcriptional activity of t of the AR. In particular it was shown that phosphorylation and activation of AR by Akt occurs primarily at low levels of androgens, which r on one The importance of Akt in stimulating cell growth in state of castration. Reduced the inhibition of the PI3K/Akt path with LY294002 DHT-induced expression of AR in LNCaP cells, w While blocking the expression of Akt dominant negative AR expression. Conversely, stimulation of LNCaP cells resulted in DHT-mediated AR activation of mTOR-independent Ngigen PI3K/Akt stimulation.
Recent data have shown that the androgen-dependent Ngigen LNCaP cells responded weakly to the inhibition of mTOR in vitro, w is During the growth of castration-2-C4 cells significantly reduced. The reintroduction of PTEN in cells C4 2 erh Ht their sensitivity to androgen ablation with bicalutimide. In addition, increased Hte phospho mTOR and phospho Akt were in LNCaP cells after av-951 475108-18-0 treatment with highly recognized by an inhibitor of androgen. Interestingly, RAD treatment with the mTOR inhibitor rapamycin or 001 led to increased activity of t of the AR transcription in both the high pass / pass androgenunabh Ngigen and low / androgen-dependent Ngigen LNCaP cells. A recently published Ffentlichter report, the clinical relevance of these in vitro results.
A comparison of hormone-sensitive matching and hormone-resistant tissue in patients with advanced CRPC have shown that increased Hte expression of the PI3K/Akt path with AR phosphorylation was w While assigned to the transition from a hormone-sensitive condition hormonerefractory. In addition, the increase in phospho Akt and phospho AR associated with decreased Ecdysone disease-free survival in each time-specific. These results suggest that, that clinical trials with inhibitors of the PI3K/Akt/mTOR Fwd Rtsbewegung, may be effectiveness h Depends largely on patient populations in terms of exposure to hormone therapy and resistance to castration. Clinical use of inhibitors for the treatment of prostate cancer PI3K/Akt/mTOR results from pr Clinical and in vitro studies suggest that, due to adverse events, current inhibitors of PI3K and Akt can be used in clinical practice nkt Descr have.
Currently, the most promising inhibitors of the road s PIK3/Akt/mTOR to treat prostate cancer by mTOR inhibitors, some of which are already in clinical use for other diseases and other malignancies. Only two compounds to inhibit the activation of Akt, perifosine and celecoxib have been investigated in clinical settings. In an attempt to investigate the effects of perifosine in patients with cancer of the CRPC was, none of the completely Ndigen or partial responses and identified only four patients had PSA stabilization for 12 weeks or more. However, it was the detection of circulating tumor cells in 11/14 of these patients is reduced after treatment. These results k Can be considerable, since the circulating tumor cells are regarded as evidence of disseminated disease, and increases in circulating tumor cells with an increased Hten survival rate correlated with patients