6-Thioguanine and Its Analogs Promote Apoptosis of Castration-Resistant Prostate Cancer Cells in a BRCA2-Dependent Manner
AbstractBackground: Mutations in the oncosuppressor gene BReast CAncer susceptibility gene 2 (BRCA2) predispose to aggressive forms of prostate cancer which show poor response to taxane-based therapy, the standard treatment for castration-resistant, aggressive prostate cancer. Herein, we addressed the question whether changes in BRCA2 expression, a potential surrogate marker for BRCA2 activity, may affect the response of castration-resistant prostate cancer cells to 6-thioguanine (6-TG), a thiopurine used in the treatment of haematological malignancies. Methods: Yeast, normal prostate cells and castration-resistant prostate cancer cells were treated with 6-TG or its analogues, in presence or absence of paclitaxel, or with olaparib, a poly-(ADP-ribose) polymerase (PARP) inhibitor currently in clinical trials for treatment of metastatic castration-resistant prostate cancer, and cell proliferation, apoptosis and androgen receptor (AR) levels were measured. Results: 6-TG inhibited cell proliferation in yeast, normal and castration-resistant prostate cancer cells but promoted apoptosis only in cancer cells. Suppression of BRCA2 expression by siRNA or shRNA increased the sensitivity to 6-TG- and olaparib-induced apoptosis but did not affect cancer cell response to taxane. Intriguingly, 6-TG reduced AR expression levels independently on BRCA2 expression. Instead, olaparib decreased AR levels only in BRCA2-knockdown prostate cancer cells. Notably, overexpression of BRCA2 resulted in resistance of castration-resistant prostate cancer cells to 6-TG-, taxane- and olaparib-based treatment but promoted sensitivity to apoptosis induced by 2-amino-6-bromopurine and 2,6–dithiopurine, two 6-TG analogues. Conclusions: Our results provide a pre-clinical rationale for the use of 6-TG in the treatment of BRCA2-deficient castration-resistant prostate cancers, and of certain 6-TG analogues for treatment of BRCA2-proficient prostate cancers. View Full-Text
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Laera, L.; Guaragnella, N.; Giannattasio, S.; Moro, L. 6-Thioguanine and Its Analogs Promote Apoptosis of Castration-Resistant Prostate Cancer Cells in a BRCA2-Dependent Manner. Cancers 2019, 11, 945.
Laera L, Guaragnella N, Giannattasio S, Moro L. 6-Thioguanine and Its Analogs Promote Apoptosis of Castration-Resistant Prostate Cancer Cells in a BRCA2-Dependent Manner. Cancers. 2019; 11(7):945.Chicago/Turabian Style
Laera, Luna; Guaragnella, Nicoletta; Giannattasio, Sergio; Moro, Loredana. 2019. "6-Thioguanine and Its Analogs Promote Apoptosis of Castration-Resistant Prostate Cancer Cells in a BRCA2-Dependent Manner." Cancers 11, no. 7: 945.
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