Survivorship and improving quality of life in men with prostate cancer

Context: Long-term survival following a diagnosis of cancer is improving in developed nations. However, living longer does not necessarily equate to living well. Objective: To search systematically and synthesise narratively the evidence from randomised controlled trials (RCTs) of supportive interventions designed to improve prostate cancer (PCa)-specific quality of life (QoL). Evidence acquisition: A systematic search of Medline and Embase was carried out from inception to July 2014 to identify interventions targeting PCa QoL outcomes. We did not include nonrandomised studies or trials of mixed cancer groups. In addition to database searches, citations from included papers were hand-searched for any potentially eligible trials. Evidence synthesis: A total of 2654 PCa survivors from 20 eligible RCTs were identified from our database searches and reference checks. Disease-specific QoL was assessed most frequently by the Functional Assessment of Cancer Therapy-Prostate questionnaire. Included studies involved men across all stages of disease. Supportive interventions that featured individually tailored approaches and supportive interaction with dedicated staff produced the most convincing evidence of a benefit for PCa-specific QoL. Much of these data come from lifestyle interventions. Our review found little supportive evidence for simple literature provision (either in booklets or via online platforms) or cognitive behavioural approaches. Conclusions: Physical and psychological health problems can have a serious negative impact on QoL in PCa survivors. Individually tailored supportive interventions such as exercise prescription/referral should be considered by multidisciplinary clinical teams where available. Cost-effectiveness data and an understanding of how to sustain benefits over the long term are important areas for future research. Patient summary: This review of supportive interventions for improving quality of life in prostate cancer survivors found that supervised and individually tailored patient-centred interventions such as lifestyle programmes are of benefit.</p

The Use of Dietary Supplements to Alleviate Androgen Deprivation Therapy Side Effects during Prostate Cancer Treatment

Prostate cancer (PCa), the most commonly diagnosed cancer and second leading cause of male cancer death in Western societies, is typically androgen-dependent, a characteristic that underlies the rationale of androgen deprivation therapy (ADT). Approximately 90% of patients initially respond to ADT strategies, however many experience side effects including hot flashes, cardiotoxicity, metabolic and musculoskeletal alterations. This review summarizes pre-clinical and clinical studies investigating the ability of dietary supplements to alleviate adverse effects arising from ADT. In particular, we focus on herbal compounds, phytoestrogens, selenium (Se), fatty acids (FA), calcium, and Vitamins D and E. Indeed, there is some evidence that calcium and Vitamin D can prevent the development of osteoporosis during ADT. On the other hand, caution should be taken with the antioxidants Se and Vitamin E until the basis underlying their respective association with type 2 diabetes mellitus and PCa tumor development has been clarified. However, many other promising supplements have not yet been subjected large-scale clinical trials making it difficult to assess their efficacy. Given the demographic trend of increased PCa diagnoses and dependence on ADT as a major therapeutic strategy, further studies are required to objectively evaluate these supplements as adjuvant for PCa patients receiving ADT

Differential Utilization of Dietary Fatty Acids in Benign and Malignant Cells of the Prostate

<div><p>Tumor cells adapt via metabolic reprogramming to meet elevated energy demands due to continuous proliferation, for example by switching to alternative energy sources. Nutrients such as glucose, fatty acids, ketone bodies and amino acids may be utilized as preferred substrates to fulfill increased energy requirements. In this study we investigated the metabolic characteristics of benign and cancer cells of the prostate with respect to their utilization of medium chain (MCTs) and long chain triglycerides (LCTs) under standard and glucose-starved culture conditions by assessing cell viability, glycolytic activity, mitochondrial respiration, the expression of genes encoding key metabolic enzymes as well as mitochondrial mass and mtDNA content. We report that BE prostate cells (RWPE-1) have a higher competence to utilize fatty acids as energy source than PCa cells (LNCaP, ABL, PC3) as shown not only by increased cell viability upon fatty acid supplementation but also by an increased ß-oxidation of fatty acids, although the base-line respiration was 2-fold higher in prostate cancer cells. Moreover, BE RWPE-1 cells were found to compensate for glucose starvation in the presence of fatty acids. Of notice, these findings were confirmed <i>in vivo</i> by showing that PCa tissue has a lower capacity in oxidizing fatty acids than benign prostate. Collectively, these metabolic differences between benign and prostate cancer cells and especially their differential utilization of fatty acids could be exploited to establish novel diagnostic and therapeutic strategies.</p></div

Primer sequences for mtDNA copy number assessment.

<p>Primer sequences for mtDNA copy number assessment.</p

Differential glycolytic activity between BE and cancer cells of the prostate.

<p>(A) A simplified overview of cellular glucose metabolism. Glucose is metabolized to pyruvate, which is either converted to acetyl CoA via pyruvate dehydrogenase (PDH) for the TCA cycle or is metabolized to lactate by lactate dehydrogenase (LDH) and excreted. Pyruvate dehydrogenase kinase 1 (PDK1) is an enzyme, which inactivates the conversion of pyruvate to acetyl-CoA to fuel the TCA cycle thereby inhibiting glucose oxidation. To evaluate glucose consumption (B) and lactate production (C), BE prostate epithelial cells (RWPE-1) and PCa cell lines (LNCaP, ABL, and PC3) were seeded in triplicates in 6 well plates under standard culture conditions. Glucose and lactate levels were measured in the supernatant after 72 h. Values denote mean expression (±SEM) relative to levels in RWPE-1 cells (set as 1.0). (D) Basal mRNA expression levels of PDK1 were determined by means of qPCR. Values are denoted relative to the housekeeping gene hydroxyl-methyl-bilane synthase (HMBS). (E) To evaluate glucose dependence, cells were seeded in triplicates in 96 well plates with indicated concentrations of glucose for 72 h. Cell viability was assessed by WST-1 assay. Values were normalized to the vehicle control (mock) in normal growth media (1g/L glucose), which was set as 1.0. All results are presented as mean ±SEM from at least three independent experiments. Statistical significance is indicated (*, P < 0.05; **, P < 0.01; ***, P < 0.001).</p

Effects of the ketone body 3-hydroxy butyrate (3-OHB) under glucose starvation.

<p>(A) Overview of cellular ketone body metabolism. Upon starvation, FAs are metabolized to ketone bodies in the liver, representing an important compensatory energy source for the cells. Oxidoreductase 3-hydroxybutyrate dehydrogenase (BDH) mediates the first step of ketone body degradation from 3-hydroxybutyrate into aceto-acetate, which is subsequently converted into two molecules of acetyl-CoA for TCA cycle. (B) Expression of BDH1, BDH2, and AACS was determined in BE (RWPE-1) and PCa cells (LNCaP, ABL, PC3) by qPCR and depicted as mean expression values relative to the housekeeping gene HMBS. (C and D) Effects of 3-OHB on cell viability under glucose starvation. Cells were cultured in 6-well plates in triplicates for 24 h prior to reduction of glucose concentrations to (C) 0.5 g/L or (D) 0.25 g/L in the absence (mock) or presence of 5 mM 3-OHB. Cell viability was assessed after 72 h using WST-1 assay. Values were normalized to vehicle control (mock) under standard growth conditions (1g/L glucose), which were set at 1.0. All results are expressed as mean values (±SEM) of three independent experiments. Significance is indicated (*, P < 0,05; **, P < 0.01; ***, P < 0.001).</p

Differential OXPHOS capacities of BE and PCa cells.

<p>BE RWPE-1 and PCa cells (LNCaP, ABL, PC3) were cultured under standard culture conditions (1g/L glucose) for 48 h. (A) Base-line respiration (ROUTINE state) was measured in intact cells and expressed as O2 flow per cells, IO2 (pmol.s-1.10–6 cells). (B and D) Substrate control factor was assessed in permeabilized cells (B) or tissue (D) and indicates the relative increase of respiration measured after subsequent titration of octanoyl-carnitine, glutamate, pyruvate and succinate in the ADP-stimulated (OXPHOS) state. (C and E) Coupling control ratios were assessed in permeabilized cells (C) and tissues (E), respectively. The L/P ratio provides a degree for coupling efficiency and the P/E ratio embodies the relative limitation of OXPHOS capacity exerted by the phosphorylation system. All results are expressed as mean value (±SEM) of three independent experiments for cultured cell lines (n = 3) and six paired BE and cancer tissue samples (n = 6). Significance is indicated (*, P < 0.05; **, P < 0.01; ***, P < 0.001)</p

BE prostate epithelial cells utilize fatty acids as preferential energy source.

<p>(A) Simplified diagram of fatty acid (FA) catabolism. FAs such as MCTs and LCTs enter the cell via FA protein transporter such as CD36 (FAT, fatty acid translocase) or via direct diffusion, respectively. In the cell, they are converted to fatty acyl CoA by fatty acyl-CoA synthetase (FACS) and further transported into the mitochondria, a step which requires carnitine palmitoyltransferase 1 (CPT1) for the transport of LCTs across the inner mitochondrial membrane. Within the mitochondria, FAs are metabolized through the FA β-oxidation pathway resulting in the production of acetyl-CoA for the TCA cycle. (B) Effects of various FAs (MCTs, LCTs, and MCTs/LCTs) on the viability of BE (RWPE-1) and PCa (LNCaP, ABL, PC3) cells were evaluated by WST-1 assay. Cells were seeded in 96 well plates in triplicates and treated with 200 μM of the indicated FAs or vehicle (mock) for 72 h. Supernatants from the same experiment were subjected to assess (C) glucose consumption and (D) lactate production via enzymatic assays as described in material and methods. All values are normalized to vehicle control (mock), which was set at 1.0. Results are expressed as mean values (±SEM) from three independent experiments. Statistical significance is indicated (*, P < 0.05; **, P < 0.01).</p

Composition of different oils employed in this study.

<p>DMSO was used as solvent to add the different oils to culture the media (20 mM stock solutions).</p><p>Composition of different oils employed in this study.</p

Subject characteristics.

<p>Subject characteristics.</p