Nutraceutical inhibitors of urokinase: potential applications in prostate cancer prevention and treatment.
Epidemiological studies have shown that the clinical incidence of prostate cancer varies by geographical area. When individuals move from low to high prostate cancer incidence areas, the risk of developing cancer increases to the level observed in the indigenous population. It was hypothesized that this observation is related to diet or more specifically to nutraceuticals present in food, medicinal plants, and herbs. Nutraceuticals can inhibit or downregulate enzymes critical for cancer formation. We tested this hypothesis by searching the 3D database of nutraceuticals and docking them to the 3D structure of urokinase. In addition to nutraceuticals, the data-base contains known uPA inhibitors that served as positive controls. From >1,000 compounds, several potential uPA inhibitors have been selected (antipain, leupeptin, folic acid, rosmarinic acid, lavendustin A, fisetin, myricetin, tolfenamic acid). Some of these were subject to further tests on inhibitory activity and inhibition of sprout formation. We found that compounds selected by computational methods indeed inhibit uPA and sprout formation. However, because the database of nutraceuticals was small, we did not expect to find either many or high affinity/specific inhibitors. Rather, we tested this method as a proof of concept. All the facts described above support the hypothesis that nutrients selected by computerized searches can inhibit unwanted uPA activity and thus reduce angiogenesis. If true, a proper diet rich in uPA-inhibiting nutraceuticals might support the prevention of prostrate cancer and be a supportive tool in prostate cancer treatment.
Jankun
Jerzy
J
Urology Research Center, Medical University of Ohio, Department of Urology, Toledo, OH 43614-5807, USA. jjankun@meduohio.edu
Selman
Steven H
SH
Aniola
Jacek
J
Skrzypczak-Jankun
Ewa
E
D002478:Cells, Cultured; D019295:Computational Biology; D004032:Diet; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000178:diet therapy* / Q000201:enzymology / Q000517:prevention & control; D011480:Protease Inhibitors / Q000008:administration & dosage* / Q000737:chemistry* / Q000302:isolation & purification; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000737:chemistry
D011480:Protease Inhibitors; D014568:Urokinase-Type Plasminogen Activator