This study was undertaken to investigate the role of purine analogues in modulating prostate cancer growth and to evaluate the potential X-linked inhibitors of apoptosis (XIAP) as a target for prostate cancer therapy. Purine analogues such as roscovitine and CGP74514A were tested in human prostate cancer models with various p53 status, LnCaP (p53 wt/wt), DU145 (p53mt/mt), and PC3 (p53null). Our results suggest that exposure to roscovitine and CGP74514A induced cell cycle arrest, mitochondria-dependent activation of caspase-9 and caspase-3 and apoptosis of both LnCaP and androgen refractory LnCaP (LnCaP-Rf) cells. The apoptosis in these cells was accompanied by stabilization of p53 and down-regulation of XIAP, but did not require inhibiton of Akt activity. Roscovitine and CGP74514A also induced down-regulation of XIAP in DU145 and PC3 cells, but moderate apoptosis was induced only when the cells were exposed to high dosage of drug, suggesting the requirement for functional p53. Accordingly, over-expression of p53 but not down-regulation of XIAP increased sensitivity of PC3 cells toward roscovitine and CGP74514A. Further, concomitant over-expression of wt p53 and down-regulation of XIAP induced apoptosis of LnCaP, DU145 and PC3 cells even in the absence of roscovitine. Together, these results suggest that lack of functional p53 and increased expression of XIAP contribute toward apoptosis-resistance in androgen-independent prostate cancer cells and should be targeted for inducing apoptosis in these cells.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]