To test a possible effect of saquinavir on the clonogenic survival of PC cells after radiation therapy, clonogenic assays were performed.Positive cells were detected in the upper right quadrant.C, DNA content of PC prostate cancer cells incubated for hwith different concentrations of saquinavir as determined by propidium iodide staining of ethanolfixed cells.Incubation with saquinavir caused concentrationdependent induction of apoptosis.The percentages of apoptotic cells in the proG peaks are indicated.Inhibition of proteasome function has been shown to induce apoptosis in cancer cells, and partial inhibition sensitizes surviving cells to the cytotoxic effects of ionizing radiation and chemotherapeutic drugs. Interestingly, the s core unit of the proteasome is the only mammalian protease known, thus far, to share specific cleavage action sites with the HIVI protease, which may be a pathogenic mechanism adopted by the virus.A recent report indicated that the HIVI PI ritonavir inhibits s proteasome function, on s and s proteasome function and the possible physiological consequences of such an inhibition in human cancer cells.It is sequestered preformed in the cytosol by inhibitor molecules of the IB family.Activation of this pathway is normally achieved by phosphorylation, polyubiquitination, and subsequent degradation by the s proteasome of one of its most important inhibitors, IB.Degradation of IB frees NFB for translocation to the nucleus and activation of its target genetic programs. We have shown that the HIVI PI saquinavir blocks NFB activation in the murine RAW macrophage and human PC prostate cancer cell lines and stabilizes IB in a concentrationdependent fashion.Because activation of NFB is an important precondition for replication and persistence of HIV, this suggests a pathway for action of saquinavir that is independent of direct viral protease inhibition.Saquinavir, like ritonavir, was shown to directly inhibit s and s proteasome function in vitro.Because the inhibition of both s and s function showed similar drug concentration dependency, we conclude that it acts on the s core unit of the proteasome.The number of colonies of each dose point was normalized to the number of colonies of the corresponding unirradiated control.Resulting survival curves were fitted using a linear quadratic model.We have previously shown that the inhibition of NFB activation in these cell lines by transduction with an IB superrepressor gene also results in apoptosis. INDUCTION OF APOPTOSIS BY SAQUINAVIR of the: ratio from. in saquinavirtreated cells.Results from two recent reports indicate that this effect is independent of the recovery of the immune system. Click on Request Permissions which will take you to the Copyright Clearance Centers Downloaded from cancerres.aacrjournals.org on April. American Association for Cancer Research. In the presence of low androgen concentrations, PKI showed profound growthinhibitory effects on tumor growth, which could be partially reversed by androgen addback.At physiological androgen concentrations, androgen withdrawal greatly enhanced the ability of PKI to retard tumor growth.About onethird of men relapse after radical prostatectomy surgery because of previously undetected metastatic disease.Metastatic prostate cancer responds for a variable period of time to androgendeprivation therapy but eventually resumes growth despite castrate levels of androgen.Several mechanisms have been proposed to explain the phenomenon of AR reactivation in the setting of castrate levels of XY1 ligand.