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6-Thioguanine and Its Analogs Promote Apoptosis of Castration-Resistant Prostate Cancer Cells in a BRCA2-Dependent Manner

1
Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Via Amendola 122/O, 70126 Bari, Italy
2
Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via Orabona 4, 70125 Bari, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2019, 11(7), 945; https://doi.org/10.3390/cancers11070945
Received: 24 June 2019 / Accepted: 3 July 2019 / Published: 5 July 2019
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Abstract

Background: 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
Keywords: prostate cancer; 6-thioguanine; paclitaxel; PARP inhibitors; BRCA2; apoptosis; yeast prostate cancer; 6-thioguanine; paclitaxel; PARP inhibitors; BRCA2; apoptosis; yeast
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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.

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