Efficacy of androgen deprivation therapy and the role of oxidative stress
Authors: D.K. Price
Journal: Annals of Oncology (2017)

Androgen deprivation therapy (ADT) is the reduction in the production and/or action of androgens by either surgical or medical castration, and is the current first-line treatment of metastatic prostate cancer. This is accomplished with anti-androgens or luteinizing hormone-releasing hormone agonists or antagonists. While initially successful, most patients will experience a biochemical recurrence within 2–5 years, with the tumors proliferating even though the patient remains at castrate levels of androgens (Figure 1). This growing population of patients with castration-resistant prostate cancer (CRPC) is faced with a drug-resistant, lethal form of prostate cancer. Although confronted with this dire situation, the hopeful news is that patients with CRPC have become the focus of recent clinical trials leading to six FDA approved agents that are available for therapeutic use. These agents include docetaxel (microtubule inhibitor, 2004) [1.Tannock I.F. de Wit R. Berry W.R. et al.Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer.N Engl J Med. 2004; 351: 1502-1512Crossref PubMed Scopus (4896) Google Scholar], sipuleucel-T (dendritic cell immunotherapy, 2010) [2.Kantoff P.W. Higano C.S. Shore N.D. et al.Sipuleucel-T immunotherapy for castration-resistant prostate cancer.N Engl J Med. 2010; 363: 411-422Crossref PubMed Scopus (4153) Google Scholar], cabazitaxel (microtubule inhibitor, 2010) [3.de Bono J.S. Oudard S. Ozguroglu M. et al.Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial.Lancet. 2010; 376: 1147-1154Abstract Full Text Full Text PDF PubMed Scopus (2600) Google Scholar], abiraterone acetate (CYP-17 inhibitor, 2012) [4.de Bono J.S. Logothetis C.J. Molina A. et al.Abiraterone and increased survival in metastatic prostate cancer.N Engl J Med. 2011; 364: 1995-2005Crossref PubMed Scopus (3391) Google Scholar], enzalutamide (androgen receptor inhibitor, 2012) [5.Scher H.I. Fizazi K. Saad F. et al.Increased survival with enzalutamide in prostate cancer after chemotherapy.N Engl J Med. 2012; 367: 1187-1197Crossref PubMed Scopus (3395) Google Scholar], and radium-223 (alpha particle radionuclide, 2013) [6.Parker C. Nilsson S. Heinrich D. et al.Alpha emitter radium-223 and survival in metastatic prostate cancer.N Engl J Med. 2013; 369: 213-223Crossref PubMed Scopus (2280) Google Scholar]. Despite these recent advances, the biology and subsequent understanding of prostate cancer metastasis and progression is still ongoing, and there is always room for more cellular targets, reliable biomarkers, therapeutic agents, and clinical options. The androgen receptor (AR) signaling axis is thought to be primarily responsible for CRPC with AR overexpression, AR gene mutations, AR splice variants, and alterations in AR co-regulators the most cited examples as the cause (reviewed by Coutinho et al. [7.Coutinho I. Day T.K. Tilley W.D. Selth LA. Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence.Endocr Relat Cancer. 2016; 23: T179-T197Crossref PubMed Scopus (113) Google Scholar]). Another recent avenue of investigation has focused on oxidative stress, reactive oxygen species (ROS), and the effect on the transcriptional activity of AR. It has previously been shown that the ROS scavenger manganese superoxide dismutase (MnSOD or SOD2) mRNA is downregulated in prostate biopsies following ADT [8.Best C.J. Gillespie J.W. Yi Y. et al.Molecular alterations in primary prostate cancer after androgen ablation therapy.Clin Cancer Res. 2005; 11: 6823-6834Crossref PubMed Scopus (148) Google Scholar], and that this down-regulation induces AR activity in a ROS-dependent manner [9.Sharifi N. Hurt E.M. Thomas S.B. Farrar WL. Effects of manganese superoxide dismutase silencing on androgen receptor function and gene regulation: implications for castration-resistant prostate cancer.Clin Cancer Res. 2008; 14: 6073-6080Crossref PubMed Scopus (41) Google Scholar]. Because of this induced AR activity and subsequent prostate cell growth, oxidative stress plays a role in castration resistance both by direct and indirect interactions (reviewed by Shiota et al. [10.Shiota M. Yokomizo A. Naito S. Oxidative stress and androgen receptor signaling in the development and progression of castration-resistant prostate cancer.Free Radic Biol Med. 2011; 51: 1320-1328Crossref PubMed Scopus (95) Google Scholar,11.Shiota M. Yokomizo A. Naito S. Pro-survival and anti-apoptotic properties of androgen receptor signaling by oxidative stress promote treatment resistance in prostate cancer.Endocr Relat Cancer. 2012; 19: R243-R253Crossref PubMed Scopus (49) Google Scholar]). Recently, much attention has been devoted to the investigation of polymorphisms in important genes in the androgen and associated pathways to better understand their contribution in both early and late stage prostate cancer. These include genes involved in androgen synthesis, signaling, and metabolism (CYPs, HSDs, SRDs), transport (SLCOs) and growth hormones and receptors (IGFs, EGFs). In this issue ofAnnals of Oncology, a group led by Shiota et al. at Kyushu University add to their impressive body of work focusing on oxidative stress and the role it plays in the development and progression of prostate cancer [12.Shiota M. Takeuchi A. Song Y. et al.Y-box binding protein-1 promotes castration-resistant prostate cancer growth via androgen receptor expression.Endocr Relat Cancer. 2011; 18: 505-517Crossref PubMed Scopus (54) Google Scholar, 13.Shiota M. Yokomizo A. Fujimoto N. Naito S. Androgen receptor cofactors in prostate cancer: potential therapeutic targets of castration-resistant prostate cancer.CCDT. 2011; 11: 870-881Crossref Scopus (36) Google Scholar, 14.Shiota M. Yokomizo A. Naito S. Increased androgen receptor transcription: a cause of castration-resistant prostate cancer and a possible therapeutic target.J Mol Endocrinol. 2011; 47: R25-R41Crossref PubMed Scopus (84) Google Scholar, 15.Shiota M. Yokomizo A. Tada Y. et al.Castration resistance of prostate cancer cells caused by castration-induced oxidative stress through Twist1 and androgen receptor overexpression.Oncogene. 2010; 29: 237-250Crossref PubMed Scopus (103) Google Scholar]. The manuscript presented in this issue reports their findings correlating polymorphisms in antioxidant enzymes with the efficacy of ADT [16.Shiota M. Fujimoto N. Itsumi M. et al.Gene polymorphisms in antioxidant enzymes correlate with the efficacy of androgen-deprivation therapy for prostate cancer with implications of oxidative stress.Ann Oncol. 2017; 28: 569-575Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar]. The authors selected nine promoter or coding region SNPs from ROS detoxifying antioxidant enzymes that included the superoxide dismutases (SODs), catalase (CAT), and glutathione S-tranferases (GSTs) in 104 Japanese men with metastatic disease previously treated with ADT. The patients studied had aggressive disease with high serum PSA levels, Gleason scores >7, stages T3 or T4, with regional or distant metastases. One SNP located in GSTM3 was significantly associated with progression-free survival and associated with a lower risk of progression to CRPC, and a SNP in CAT was significantly associated with a lower risk of all-cause death. To further validate their findings, a set of 92 men treated with ADT for biochemical recurrence after primary therapy that did not have metastatic prostate cancer was used. These men had lower PSA levels, Gleason scores, and stages at diagnosis. A lower risk of progression and all-cause death was observed for a specific allele in GSTM3 in this set as well. While the authors admit to shortcomings in their retrospective study that include sample size, and only one population, the findings of polymorphisms in antioxidant enzyme genes associated with efficacy of ADT is important, and will continue to be a robust avenue of research. A follow-up study using a large, ethnically diverse population to validate these initial findings is needed. A main focus for many, if not all, prostate cancer researchers is to better understand the progression of the disease, and to discover the clues that will help answer the question of which men will develop aggressive life-threatening disease, as opposed to those that have a systemic, but non-aggressive form. Shiota et al. may have provided a new bio-marker that helps to predict the outcome of initial hormonal treatment. This study adds to the literature demonstrating the importance of oxidative stress in CRPC, and highlights the possible use of antioxidant therapy in clinical management. It is interesting to speculate that the use of an antioxidant likeN-acetylcysteine, which has been shown to reverse the down-regulation of ROS regulating genes like SOD2 [9.Sharifi N. Hurt E.M. Thomas S.B. Farrar WL. Effects of manganese superoxide dismutase silencing on androgen receptor function and gene regulation: implications for castration-resistant prostate cancer.Clin Cancer Res. 2008; 14: 6073-6080Crossref PubMed Scopus (41) Google Scholar] may find use in combination with the current arsenal of agents to help silence AR activity in patients with CRPC. It is through the study and understanding of the disease at the cellular level that will lead to potential new therapeutic targets and clinically useful bio-markers. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. Government. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. No grant numbers apply.