INDUCTION OF APOPTOSIS IN ANDROGEN-INDEPENDENT HUMAN PROSTATE-CANCER CELLS UNDERGOING THYMINELESS DEATH

Previous studies have demonstrated that androgen responsive human pros tate cancer cells can be induced to undergo programmed cell death afte r androgen ablation. By contrast, androgen-independent human prostate cancer cells do not activate this apoptotic pathway in response to and rogen ablation. In the present study, two androgen-independent human p rostatic cell lines, PC-3 and DU-145, were used as in vitro model syst ems to investigate the possibility of induction of programmed cell dea th in response to non-androgen ablative cytotoxic drugs. Treatment of these cells with the fluorinated pyrimidines, 5-fluoro-2-deoxyuridine or trifluorothymidine, resulted in a significant decrease in cell viab ility, over a period of 96 hr of exposure to the drugs, as determined by the trypan blue exclusion assay. The characteristic DNA fragmentati on into a nucleosomal ladder and induction of expression of specific a poptosis-related genes, such as TRPM-2/SGP-2, and TGF-beta(1), but not the growth-related genes, c-myc, c-fos, and p53, temporally correlate d with activation of apoptotic cell death in both systems. Simultaneou s treatment with exogenous thymidine completely abrogated the fluoropy rimidine-induced cytotoxic effect in both cell lines, as well as the n ucleosomal fragmentation of DNA, indicating that this apoptotic proces s is due to the induction of ''thymineless'' state. These results sugg est that androgen-independent human prostate cancer cells retain the a bility to activate the apoptotic cascade, after treatment with cytotox ic drugs that induce a ''thymineless'' state. (C) 1994 Wiley-Liss, Inc .