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

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