The effects of the inhibition of inducible nitric oxide synthase on angiogenesis of epithelial ovarian cancer.
OBJECTIVE
The release of nitric oxide by tumor cells, through the stimulation of inducible nitric oxide synthase expression, may play a critical role in ovarian cancer progression. In this study we have sought to determine the effects of inhibiting inducible nitric oxide synthase on angiogenesis that was induced by 2 ovarian cancer cell lines, SKOV and MDAH2774.


METHODS
Real-time polymerase chain reaction and enzyme-linked immunosorbent assay techniques were used to determine the expression levels of inducible nitric oxide synthase and vascular endothelial growth factor in the ovarian cancer cell lines in response to treatments with L-NAME, an inhibitor of nitric oxide synthase, and SNAP, and nitric oxide donor. Ovarian cancer-induced angiogenesis was assessed in vitro with an established assay that is based on the ability of human umbilical vein endothelial cells to form a tubular network in response to angiogenic agents.


RESULTS
SKOV and MDAH2774 cell lines exhibited over-expression of inducible nitric oxide synthase and have high baseline nitric oxide levels. This was associated with high levels of vascular endothelial growth factor production and angiogenesis induction. Treatment of the ovarian cancer cell lines with L-NAME significantly reduced vascular endothelial growth factor levels production and completely inhibited angiogenesis. In contrast, treatment with SNAP significantly increased vascular endothelial growth factor levels and increased angiogenesis in both cell lines.


CONCLUSIONS
Our data suggest that the inhibition of inducible nitric oxide synthase may form a basis for a novel therapeutic treatment option for ovarian cancer therapy.
Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201, USA. jmalone@dmc.org
John M
JM
Malone
Ghassan M
GM
Saed
Michael P
MP
Diamond
Robert J
RJ
Sokol
Adnan R
AR
Munkarah
D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D019331:NG-Nitroarginine Methyl Ester / Q000627:therapeutic use*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D014471:Umbilical Veins
D004791:Enzyme Inhibitors; D052247:Nitric Oxide Synthase Type II; D019331:NG-Nitroarginine Methyl Ester