title: Inhibition of XO or NOX attenuates diethylstilbestrol-induced endothelial nitric oxide deficiency without affecting its effects on LNCaP cell invasion and apoptosis.
abstract: Oestrogen protects cardiovascular health partially via an up-regulation of NO• (NO radical) production. Its synthetic analogue DES (diethylstilbestrol), used as a potent androgen deprivation therapy for patients with prostate cancer, is however associated with high incidence of thromboembolic events. Exposure of BAECs (bovine aortic endothelial cells) to pharmacologically relevant dosage (12.5 μmol/l, 24 h) of DES resulted in a marked reduction in endothelial NO• bioavailability determined by ESR (electron spin resonance), while 17β-oestradiol instead increased NO• production as expected. Intriguingly, endothelial O(2)•- (superoxide anion) production was up-regulated by DES in vitro and in vivo, which was, however, attenuated by the ER (oestrogen receptor) antagonist ICI 182780, the XO (xanthine oxidase) inhibitor oxypurinol or the NOX (NADPH oxidase) inhibitor NSC23766. These agents also restored NO• production. DES alone in a cell-free system did not produce any ESR-sound O(2)•- signal. Of note, eNOS (endothelial NO synthase) mRNA and protein remained unchanged in response to DES. These results suggest that receptor-dependent activation of XO or NOX, and subsequent production of O(2)•-, mediate DES-induced NO• deficiency. This could represent a previously unrecognized mechanism that is responsible for cardiovascular complications of DES administration. Importantly, DES-induced suppression of LNCaP cell invasion and apoptosis were not affected by XO or NOX inhibitor. Therefore combinatorial therapy of DES and XO/NOX inhibitor may prove to be an innovative and useful therapeutic option in eliminating cardiovascular complications of DES, while preserving its anti-cancer effects, benefiting patients with advanced cancer who do not respond well to any other treatments but DES.
authors.affiliation: Division of Molecular Medicine, Cardiovascular Research Laboratories, Departments of Anesthesiology and Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095, U.S.A.
authors.forename: Ji-Youn
authors.initials: JY
authors.lastname: Youn
authors.forename: Andrew
authors.initials: A
authors.lastname: Nguyen
authors.forename: Hua
authors.initials: H
authors.lastname: Cai
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002417:Cattle; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004054:Diethylstilbestrol / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000172:deficiency*; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis / Q000235:genetics; D010117:Oxypurinol / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000473:pathology*; D011743:Pyrimidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D000634:Aminoquinolines; D004791:Enzyme Inhibitors; C487513:NSC 23766; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D013481:Superoxides; D009569:Nitric Oxide; D004054:Diethylstilbestrol; D006861:Hydrogen Peroxide; D052250:Nitric Oxide Synthase Type III; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D010117:Oxypurinol