title: Effects of flavocoxid, a dual inhibitor of COX and 5-lipoxygenase enzymes, on benign prostatic hyperplasia.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, University of Messina, Messina, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Altavilla
authors.forename: L
authors.initials: L
authors.lastname: Minutoli
authors.forename: F
authors.initials: F
authors.lastname: Polito
authors.forename: N
authors.initials: N
authors.lastname: Irrera
authors.forename: S
authors.initials: S
authors.lastname: Arena
authors.forename: C
authors.initials: C
authors.lastname: Magno
authors.forename: M
authors.initials: M
authors.lastname: Rinaldi
authors.forename: B P
authors.initials: BP
authors.lastname: Burnett
authors.forename: F
authors.initials: F
authors.lastname: Squadrito
authors.forename: A
authors.initials: A
authors.lastname: Bitto
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002392:Catechin / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015232:Dinoprostone / Q000378:metabolism; D004338:Drug Combinations; D004815:Epidermal Growth Factor / Q000235:genetics; D006801:Humans; D007975:Leukotriene B4 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D011470:Prostatic Hyperplasia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494828:Bax protein, rat; D016861:Cyclooxygenase Inhibitors; D004338:Drug Combinations; D016859:Lipoxygenase Inhibitors; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D051028:bcl-2-Associated X Protein; C544478:flavocoxid; C467498:vascular endothelial growth factor A, rat; D007975:Leukotriene B4; D004815:Epidermal Growth Factor; D002392:Catechin; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D053453:Caspase 9; D015232:Dinoprostone