Food Microbiology

More than 70% of prostate cancer (PCa) patients display loss or reduction of BRCA2 protein, an onco-suppressor involved in DNA repair through homologous recombination. We have shown that loss of BRCA2 confers cells resistance to anoikis, a peculiar form of programmed cell death (PCD) necessary for cancer cells to colonize distal sites during the metastatic process. This PCD-promoting function of BRCA2 is conserved in the yeast Saccharomyces cerevisiae. Patients with metastatic PCa display only temporary disease control following androgen deprivation but they eventually develop disease progression to virtually incurable castration-resistant prostate cancer (CRPC). We used yeast expressing BRCA2, normal prostate cell and a CRPC cell line model for a pre-clinical toxicity screening of 6-thioguanine (6-TG) and six 6-TG analogues. We found that 6-TG decreased proliferation in yeast preferably in the presence of BRCA2 and normal prostate cells without inducing cell death. Strikingly, 6-TG not only impaired cell proliferation but also induced significant cell death in CRPC cells by activating a PCD program. Silencing of BRCA2 expression increased CPRC cell sensitivity to 6-TG-induced cell death. 2,6-dithiopurine (2,6DTP) strongly decreased proliferation and induced cell death in yeast independently of BRCA2. 2,6DTP and 2-amino-6-bromopurine selectively induced PCD in BRCA2-expressing CPRC cells. These results suggest the potential use of 6-TG and its analogues for the treatment of CRPC alone or in combination with taxanes, chemotherapeutic drugs approved for CRPC treatment.