Molecular Targeting of the PI3K/Akt Pathway to Prevent the Development of Hormone Resistant Prostate Cancer

摘要

Recently, the PI3K/Akt pathway has been found to be a significant factor in the development and progression of prostate cancer. It is the authors' belief that the PI3K/Akt pathway is the critical pathway that is maintaining survival by blocking apoptosis in the absence of hormonal stimulation. They will use molecular targeting to inhibit the phosphorylation of Akt. Celecoxib is a FDA approved COX-2 inhibitor. What is unique to celecoxib is its ability to inhibit the phosphorylation of Akt. This effectively turns off the PI3k/Akt pathway leading to apoptosis. Celecoxib has been shown to induce apoptosis in a number of different malignancies. Unfortunately, the half maximal inhibitory concentration (IC(sub 50)) of celecoxib is less than is usually obtainable clinically. Therefore, in an attempt to improve upon Akt activity and decrease the IC(sub 50) concentration to clinically obtainable levels, Chin et al. synthesized multiple 2nd and 3rd generation compounds. These newer compounds have significantly lower IC(sub 50) levels, thus, therapeutic levels can be obtained clinically. The authors will use celecoxib and these newer compounds to evaluate the effects of combined PI3K/Akt inhibition and androgen ablation.