Of PI3K. Treatment with lower phospho Akt in av-951 Tivozanib wortmannin PC 3 and LNCaP cells, and induces apoptosis and radiosensitized DU 145 cells. Wortmannin, Similar to LY294002, is not specific to PI3K and inhibits several other signaling molecules. Unfortunately, the use of both in vivo, LY294002 and wortmannin, have faced significant negative side effects. Nevertheless, in vivo, LY294002 decreased phosphorylation of eIF4F and translation of proteins downstream Rts in the prostate gland of transgenic mice M, A constitutively active catalytic subunit of PI3K. Lately it has been shown that curcumin inhibits PI3K activity to t, additionally Tzlich to other mechanisms of action. Treatment of curcumin-induced apoptosis of LNCaP, PC-3 and DU-145 cells, inhibits the growth of LNCaP and PC 3 xenografts and inhibits the formation of PIN in TRAMP mice M-.
Accordingly, in view of the crucial role of PI3K in cancer therapy and the limited availability of specific inhibitors, there are several new inhibitors of PI3K in the development, the selectivity of t obtained have Ht against PI3K, but they have not yet been evaluated in prostate cancer. Several inhibitors of Akt examined in prostate cancer. Perifosine is a alkylphospholipid, WZ8040 EGFR inhibitor which decreases the phosphorylation of Akt and up-regulated the expression of the p21 tumor suppressor. Perifosine inhibited growth and induced cell cycle arrest of PC3 cells, and it also induces the differentiation of PC 3 and LNCaP cells by activation of GSK third Although there are no clinical studies examining perifosine effect against prostate cancer VER Was published, perifosine occurred in clinical trials in prostate cancer.
Genistein, a isoflavinoid found in soybeans, is another compound with inhibitory effect of act In vitro studies have shown that genistein, the activity T inhibited by Akt and caused significant growth inhibition and apoptosis of prostate cancer cells. However, genistein also inhibits mTOR, AR, and a wide range of other targets. In vivo, genistein has big potential there, raising awareness DCC-2036 of prostate tumors to radiation and showed a decreased incidence of lung metastasis in an orthotopic model of PC 3 cells. In an experimental model of bone metastases, genistein, in combination with docetaxel inhibited growth in both medium alone. Interestingly, in a report that genistein increased Ht the size E of metastatic lymph nodes in an orthotopic model of PC-3.
Celecoxib, a known inhibitor of cyclooxygenase-2, also inhibits the phosphorylation of Akt prostate cancer cells, and can chemopr Preventive properties have shown to reduce, as indicated by their F Ability, the formation of PIN and adenocarcinoma in a mouse model of prostate cancer and rat. However, because of the many activity Th of celecoxib, k The observed effects may be not only to an inhibition of Akt returned. To further delineate the anti-Akt activity t of celecoxib, a structural analogue of celecoxib dimethylcelecoxib, which was not developed on inhibitory activity of COX-2. The administration of DMC to tumor-bearing animals has entered 3 PC Born inhibition of phosphorylation of Akt, but also in the inhibition of PDK1 and was accompanied by decreased tumor growth. There are two other Erg Nzungen to the family of inhibitors of Akt, Deguelin and GSK690693. Deguelin a rotenoid, has been shown to act Activati Inhibit