leukotriene-b4 and Prostatic-Hyperplasia

Inflammation plays a key role in the development of benign prostatic hyperplasia (BPH). Eicosanoids derived from the COX and 5-lipoxygenase (5-LOX) pathways are elevated in the enlarging prostate. Flavocoxid is a novel flavonoid-based 'dual inhibitor' of the COX and 5-LOX enzymes. This study evaluated the effects of flavocoxid in experimental BPH.. Rats were treated daily with testosterone propionate (3 mg·kg(-1)  s.c.) or its vehicle for 14 days to induce BPH. Animals receiving testosterone were randomized to receive vehicle (1 mL·kg(-1) , i.p.) or flavocoxid (20 mg·kg(-1) , i.p.) for 14 days. Histological changes, eicosanoid content and mRNA and protein levels for apoptosis-related proteins and growth factors were assayed in prostate tissue. The effects of flavocoxid were also tested on human prostate carcinoma PC3 cells.. Flavocoxid reduced prostate weight and hyperplasia, blunted inducible expression of COX-2 and 5-LOX as well as the increased production of PGE(2) and leukotriene B(4) (LTB(4) ), enhanced pro-apoptotic Bax and caspase-9 and decreased the anti-apoptotic Bcl-2 mRNA. Flavocoxid also reduced EGF and VEGF expression. In PC3 cells, flavocoxid stimulated apoptosis and inhibited growth factor expression. Flavocoxid-mediated induction of apoptosis was inhibited by the pan-caspase inhibitor, Z-VAD-FMK, in PC3 cells, suggesting an essential role of caspases in flavocoxid-mediated apoptosis during prostatic growth.. Our results show that a 'dual inhibitor' of the COX and 5-LOX enzymes, such as flavocoxid, might represent a rational approach to reduce BPH through modulation of eicosanoid production and a caspase-induced apoptotic mechanism.

Topics: Animals; Apoptosis; Arachidonate 5-Lipoxygenase; bcl-2-Associated X Protein; Caspase 9; Catechin; Cell Line, Tumor; Cell Survival; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dinoprostone; Drug Combinations; Epidermal Growth Factor; Humans; Leukotriene B4; Lipoxygenase Inhibitors; Male; Prostatic Hyperplasia; Rats; Rats, Sprague-Dawley; RNA, Messenger; Vascular Endothelial Growth Factor A

PGE2 and LTB4 are involved in inflammation and carcinogenesis in several tissues but have not been studied in prostate cancer and hyperplasia until now. We therefore measured PGE2 and LTB4 productions in a total of 206 prostate tissues from 116 patients including benign hyperplastic (90), pericancerous (106) and cancerous samples (10). We also analysed the influence of inflammation levels, prostate volume and glandular to epithelial ratio. PGE2 and LTB4 concentrations were measured using specific enzyme immunoassay kits. There was a correlation between PGE2 level, prostatic volume, inflammation score, and decreased glandular surface. By contrast, there was no correlation between LTB4 levels and inflammation or PGE2 production. Cancerous samples had higher LTB4 levels than pericancerous samples, but there was no difference in PGE2 levels. PGE2 and inflammation may be associated to stromal benign prostatic hyperplasia whereas LTB4 may play a role in prostate carcinogenesis.

Topics: Adult; Aged; Aged, 80 and over; Dinoprostone; Humans; Inflammation; Leukotriene B4; Male; Middle Aged; Organ Size; Prostatic Hyperplasia; Prostatic Neoplasms

Although the lipidic extract of Serenoa repens (LESSr, Permixon, Sereprostat) is widely used in patients suffering from benign prostatic hypertrophy (BPH), its mechanism of action is not fully elucidated. It has been demonstrated that infiltration of the prostate by inflammatory cells is one of the aetiologic factors involved in the development of BPH. These inflammatory cell types, such as polymorphonuclear neutrophils (PMNs), produce chemotactic mediators and contribute to the development of the disease. Among the chemotactic factors generated by inflammatory cell types, the derivatives of arachidonic acid have been extensively studied. For instance, leukotriene (LT) B4 is one of the most potent chemotactic factors for PMNs and also exhibits a wide range of biological activities. In order to investigate the potential action of LESSr on arachidonate metabolism, and particularly on the synthesis of LTB4, the effect of this extract on the in vitro synthesis of LT by human PMNs stimulated with the calcium ionophore A23187 was investigated. LESSr significantly inhibits the production of 5-lipoxygenase metabolites (5-HETE, 20-COOH LTB4, LTB4 and 20-OH LTB4) at concentrations as low as 5 microg/ml. Such an effect of LESSr was also observed in the presence of exogenous arachidonic acid (20 microg/ml) and when f-MLP was used as the agonist, suggesting that inhibition of LTB4 production by the extract was unrelated to phospholipase A2 blockade and independent of the stimulating agent. The capability of LESSr to antagonize 5-lipoxygenase metabolites production may contribute, at least partly, to the understanding of its therapeutic activity on the inflammatory component of BPH.

Topics: Arachidonate 5-Lipoxygenase; Calcimycin; Cell Survival; Humans; Ionophores; Leukotriene B4; Male; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Plant Extracts; Prostatic Hyperplasia; Serenoa