Effects of Flavocoxid, a Dual Inhibitor of Cyclooxygenase and 5-Lipoxygenase Enzymes, on Benign Prostatic Hyperplasia
Altavilla D, Minutoli L, Polito F, Irrera N, Arena S, Magno C, Rinaldi M, Burnett BP, Squadrito F, Bitto A. Br J Pharmacol. 2012 Apr 3. doi: 10.1111/j.1476-5381.2012.01969.x. [Epub ahead of print]


Department of Clinical and Experimental Medicine and Pharmacology -Section of Pharmacology- University of Messina, Messina, Italy. Department of Biochemical, Physiological and Nutritional Sciences, Section of Physiology and Human Nutrition, University of Messina, Italy. Department of Urology, University of Messina, Messina, Italy. Department of Medical Affairs, Primus Pharmaceuticals Inc., Scottsdale, AZ.


Background and Purpose:  Inflammation plays a key role in the development of benign prostatic hyperplasia (BPH). Products derived from the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) are significantly elevated in the enlarging prostate. Flavocoxid is a novel flavonoid-based "dual inhibitor" of the COX and 5-LOX enzymes. This study was designed to evaluate the effects of flavocoxid in experimental BPH. Experimental approach:  Rats were treated daily with testosterone propionate (3 mg kg(-1 ) s.c.) or its vehicle for 14 days. Testosterone administered animals were randomized to receive vehicle (1 ml kg(-1) , i.p.) or flavocoxid (20 mg kg(-1) , i.p.) for 14 days. The effects of flavocoxid were also tested on human prostate carcinoma PC3 cells. Key results:  Flavocoxid reduced prostate weight and hyperplasia, blunted inducible expression of COX-2 and 5-LOX as well as the increased production of prostaglandin E2 (PGE(2) ) and leukotriene B4 (LTB(4) ), enhanced pro-apoptotic Bax and caspase-9 and decreased the anti-apoptotic Bcl-2 mRNA. Flavocoxid also reduced epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) expression. In PC3 cells, flavocoxid-stimulated apoptosis and inhibited growth factor expression. Flavocoxid-mediated induction of apoptosis was significantly blunted by the pan-caspase inhibitor, Z-VAD-FMK, in PC3 cells suggesting an essential role of caspases in flavocoxid-mediated apoptosis during prostatic growth. Conclusion and Implications:  The present study shows that a "dual inhibitor" of the COX and 5-LOX enzymes, such as flavocoxid, might represent a rational approach to reduce benign prostate hyperplasia through modulation of fatty acid production and a caspase-induced apoptotic mechanism.