Drug discovery in advanced prostate cancer: translating biology into therapy.

Castration-resistant prostate cancer (CRPC) is associated with a poor prognosis and poses considerable therapeutic challenges. Recent genetic and technological advances have provided insights into prostate cancer biology and have enabled the identification of novel drug targets and potent molecularly targeted therapeutics for this disease. In this article, we review recent advances in prostate cancer target identification for drug discovery and discuss their promise and associated challenges. We review the evolving therapeutic landscape of CRPC and discuss issues associated with precision medicine as well as challenges encountered with immunotherapy for this disease. Finally, we envision the future management of CRPC, highlighting the use of circulating biomarkers and modern clinical trial designs

Epigenetic modulators as therapeutic targets in prostate cancer

Prostate cancer is one of the most common non-cutaneous malignancies among men worldwide. Epigenetic aberrations, including changes in DNA methylation patterns and/or histone modifications, are key drivers of prostate carcinogenesis. These epigenetic defects might be due to deregulated function and/or expression of the epigenetic machinery, affecting the expression of several important genes. Remarkably, epigenetic modifications are reversible and numerous compounds that target the epigenetic enzymes and regulatory proteins were reported to be effective in cancer growth control. In fact, some of these drugs are already being tested in clinical trials. This review discusses the most important epigenetic alterations in prostate cancer, highlighting the role of epigenetic modulating compounds in pre-clinical and clinical trials as potential therapeutic agents for prostate cancer management.info:eu-repo/semantics/publishedVersio

Food utilisation and digestive ability of aquatic and semi-terrestrial crayfishes, Cherax destructor and Engaeus sericatus (Astacidae, Parastacidae)

Both Engaeus sericatus and Cherax destructor are omnivorous crayfishes consuming a variety of food items. Materials identified in the faeces of both E. sericatus and C. destructor consisted of mainly plant material with minor amounts of arthropod animals, algae and fungi. The morphology of the gastric mill of C. destructor suggests that it is mainly involved in crushing of food material while the gastric mill of E. sericatus appears to be better suited to cutting of food material. Given this, the gastric mill of E. sericatus may be better able to cut the cellulose and hemicellulose fibres associated with fibrous plant material. In contrast, the gastric mill of C. destructor appears to be more efficient in grinding soft materials such as animal protein and algae. Both species accumulated high amounts of lipids in their midgut glands (about 60% of the dry mass) which were dominated by triacylglycerols (81&ndash;82% of total lipids). The dominating fatty acids were 16:0, 16:1(n-7), 18:1(n-9), 18:2(n-6), and 18:3(n-3). The two latter fatty acids can only be synthesised by plants, and are thus indicative of the consumption of terrestrial plants by the crayfishes. The similarity analysis of the fatty acid patterns showed three distinct clusters of plants and each of the crayfish species. The complement of digestive enzymes, proteinases, total cellulase, endo-&beta;-1,4-glucanase, &beta;-glucosidase, laminarinase and xylanase within midgut gland suggests that both C. destructor and E. sericatus are capable of hydrolysing a variety of substrates associated with an omnivorous diet. Higher activities of total cellulase, endo-&beta;-1,4-glucanase and &beta;-glucosidase indicate that E. sericatus is better able to hydrolyse cellulose within plant material than C. destructor. In contrast to E. sericatus, higher total protease and N-acetyl-&beta;-d-glucosaminidase activity in the midgut gland of C. destructor suggests that this species is better able to digest animal materials in the form of arthropods. Differences in total cellulase and gastric mill morphology suggest that E. sericatus is more efficient at digesting plant material than C. destructor. However, the contents of faecal pellets and the fatty acid compositions seem to indicate that both species opportunistically feed on the most abundant and easily accessible food items.<br /

Macrobrachium borellii Hepatopancreas Contains a Mitochondrial Glycerol-3-Phosphate Acyltransferase Which Initiates Triacylglycerol Biosynthesis

Mammals express four isoforms of glycerol-3-phosphate acyltransferase (GPAT). The mitochondrial isoform GPAT1 may have been the acyltransferase that appeared first in evolution. The hepatopancreas of the crustacean Macrobrachium borellii has a high capacity for triacylglycerol (TAG) biosynthesis and storage. In order to understand the mechanism of glycerolipid biosynthesis in M. borellii, we investigated its hepatopancreas GPAT activity. In hepatopancreas mitochondria, we identified a GPAT activity with characteristics similar to those of mammalian GPAT1. The activity was resistant to inactivation by SH-reactive N-ethylmaleimide, it was activated by polymyxin-B, and its preferred substrate was palmitoyl-CoA. The reaction products were similar to those of mammalian GPAT1. A 70-kDa protein band immunoreacted with an anti-rat liver GPAT1 antibody. Surprisingly, we did not detect high GPAT specific activity in hepato-pancreas microsomes. GPAT activity in microsomes was consistent with mitochondrial contamination, and its properties were similar to those of the mitochondrial activity. In microsomes, TAG synthesis was not dependent on the presence of glycerol-3 phosphate as a substrate, and the addition of monoacylglycerol as a substrate increased TAG synthesis 2-fold. We conclude that in M. borellii the de novo triacylglycerol biosynthetic pathway can be completed in the mitochondria. In contrast, TAG synthesis in the ER may function via the monoacylglycerol pathway