Endostatin inhibits nitric oxide and diminishes VEGF and collagen XVIII in squamous carcinoma cells.
Low pO(2) values are a common finding among oral squamous cell carcinomas (SCC). Our objective was to determine the role that oxygen tension plays on the direct tumor effect of endostatin (ES). Squamous carcinoma cell lines were grown under normoxic or hypoxic conditions and treated with endostatin (ES), nitric oxide (NO) donors, NO scavengers, NO synthase inhibitors, or transduced with AdenoVec-hEndo or AdenoVec Null vectors. The expression of vascular endothelial growth factor (VEGF) and collagen XVIII were determined by RT-PCR and protein levels assessed by Western blot analyses. Our studies demonstrated that collagen XVIII and VEGF are expressed and responsive to ES in a limited number of SCC cell lines during normoxia but were most responsive when grown under hypoxic conditions. VEGF and collagen XVIII were downregulated by both ES and transduction of cells with AdenoVec-hEndo. The effects of ES on SCC cells were enhanced by aminoguanidine (Ag), L-NAME, and diphenyleneiodonium chloride (DPI). Endostatin and transduced with ES vectors diminished the levels of NO whereas NO donors enhanced VEGF expression and collagen XVIII expression. In conclusion, the direct effect of endostatins on tumor cells is most effective under conditions of low oxygen tension and can be potentiated by the use of nitric oxide synthase inhibitors or NO scavengers.
Hebert
Carla
C
Department of Diagnostic Sciences and Pathology, University of Maryland-Baltimore, 666 W. Baltimore Street, Baltimore, MD 21201, USA.
Siavash
Hessam
H
Norris
Kathleen
K
Nikitakis
Nikolaos G
NG
Sauk
John J
JJ
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D043170:Collagen Type XVIII / Q000235:genetics*; D017931:DNA Primers; D043169:Endostatins / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D016133:Polymerase Chain Reaction / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D043170:Collagen Type XVIII; D017931:DNA Primers; D043169:Endostatins; D020030:Nitric Oxide Donors; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide