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A mounting body of evidence suggests that increased production of reactive oxygen species (ROS) is linked to aging processes and to the etiopathogenesis of aging-related diseases, such as cancer, diabetes, atherosclerosis and degenerative diseases like Parkinson's and Alzheimer's. Excess ROS are deleterious to normal cells, while in cancer cells, they can lead to accelerated tumorigenesis. In prostate cancer (PC), oxidative stress, an innate key event characterized by supraphysiological ROS concentrations, has been identified as one of the hallmarks of the aggressive disease phenotype. Specifically, oxidative stress is associated with PC development, progression and the response to therapy. Nevertheless, a thorough understanding of the relationships between oxidative stress, redox homeostasis and the activation of proliferation and survival pathways in healthy and malignant prostate remains elusive. Moreover, the failure of chemoprevention strategies targeting oxidative stress reduced the level of interest in the field after the recent negative results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) trial. Therefore, a revisit of the concept is warranted and several key issues need to be addressed: The consequences of changes in ROS levels with respect to altered redox homeostasis and redox-regulated processes in PC need to be established. Similarly, the key molecular events that cause changes in the generation of ROS in PC and the role for therapeutic strategies aimed at ameliorating oxidative stress need to be identified. Moreover, the issues whether genetic/epigenetic susceptibility for oxidative stress-induced prostatic carcinogenesis is an individual phenomenon and what measurements adequately quantify prostatic oxidative stress are also crucial. Addressing these matters will provide a more rational basis to improve the design of redox-related clinical trials in PC. This review summarizes accepted concepts and principles in redox research, and explores their implications and limitations in PC.

Bone is one of the most frequent sites for metastasis in breast cancer patients often resulting in significant clinical morbidity and mortality. Bisphosphonates are currently the standard of care for breast cancer patients with bone metastasis. We have shown previously that doxycycline, a member of the tetracycline family of antibiotics, reduces total tumour burden in an experimental bone metastasis mouse model of human breast cancer. In this study, we combined doxycycline treatment together with zoledronic acid, the most potent bisphosphonate. Drug administration started 3 days before the injection of the MDA-MB-231 cells. When mice were administered zoledronic acid alone, the total tumour burden decreased by 43% compared to placebo treatment. Administration of a combination of zoledronic acid and doxycycline resulted in a 74% decrease in total tumour burden compared to untreated mice. In doxycycline-and zoledronate-treated mice bone formation was significantly enhanced as determined by increased numbers of osteoblasts, osteoid surface and volume, whereas a decrease in bone resorption was also observed. Doxycycline greatly reduced tumour burden and could also compensate for the increased bone resorption. The addition of zoledronate to the regimen further decreased tumour burden, caused an extensive decrease in bone-associated soft tissue tumour burden (93%), and sustained the bone volume, which could result in a smaller fracture risk. Treatment with zoledronic acid in combination with doxycycline may be very beneficial for breast cancer patients at risk for osteolytic bone metastasis.

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Abstract:The low specificity of the prostate-specific antigen (PSA) for early detection of prostate cancer (PCa) is a major issue worldwide. The aim of this study to examine whether the serum PCa-associated α2,3-linked sialyl N-glycan-carrying PSA (S2,3PSA) ratio measured by automated micro-total immunoassay systems (µTAS system) can be applied as a diagnostic marker of PCa. The µTAS system can utilize affinity-based separation involving noncovalent interaction between the immunocomplex of S2,3PSA and Maackia amurensis lectin to simultaneously determine concentrations of free PSA and S2,3PSA. To validate quantitative performance, both recombinant S2,3PSA and benign-associated α2,6-linked sialyl N-glycan-carrying PSA (S2,6PSA) purified from culture supernatant of PSA cDNA transiently-transfected Chinese hamster ovary (CHO)-K1 cells were used as standard protein. Between 2007 and 2016, fifty patients with biopsy-proven PCa were pair-matched for age and PSA levels, with the same number of benign prostatic hyperplasia (BPH) patients used to validate the diagnostic performance of serum S2,3PSA ratio. A recombinant S2,3PSA-and S2,6PSA-spiked sample was clearly discriminated by µTAS system. Limit of detection of S2,3PSA was 0.05 ng/mL and coefficient variation was less than 3.1%. The area under the curve (AUC) for detection of PCa for the S2,3PSA ratio (%S2,3PSA) with cutoff value 43.85% (AUC; 0.8340) was much superior to total PSA (AUC; 0.5062) using validation sample set. Although the present results are preliminary, the newly developed µTAS platform for measuring %S2,3PSA can achieve the required assay performance specifications for use in the practical and clinical setting and may improve the accuracy of PCa diagnosis. Additional validation studies are warranted.

Abstract:The past decade has brought increased awareness of the potential adverse effects of androgen deprivation therapy (ADT) in men with prostate cancer. Arguably the most important and controversial of these is the increased risk of cardiovascular morbidity and mortality. Although multiple observational studies have shown that men treated with ADT are at increased risk of developing atherosclerotic cardiovascular disease, our understanding of the biological mechanisms that might underlie this phenomenon is still evolving. In this review, we discuss some of the mechanisms that have been proposed to date, including ADTinduced metabolic changes that promote the development and progression of atherosclerotic plaques as well as direct local effects of hormonal factors on plaque growth, rupture and thrombosis.

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Independently evaluating changes in glucose metabolism near the time of prostate cancer diagnosis and during long-term ADT treatment is important to distinguish their unique contributions to the development of metabolic disturbances. Integrative approaches, including metabolic, clinical and body composition measures, are needed to understand the role of adiposity and insulin resistance in prostate cancer and to develop effective nutrition and exercise interventions to improve secondary diseases in survivorship.