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Carcinogenesis Advance Access published online on June 9, 2008
Carcinogenesis, doi:10.1093/carcin/bgn127
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

NO-donating aspirin inhibits angiogenesis by suppressing VEGF expression in HT-29 human colon cancer mouse xenografts

Nengtai Ouyang, Jennie L. Williams and Basil Rigas

Division of Cancer Prevention, Stony Brook University, Stony Brook, NY 11794

Corresponding author: Basil Rigas, Division of Cancer Prevention, SUNY at Stony Brook, Life Sciences Building, Room 006, Stony Brook, NY 11794-5200. Tel: 631-632-9035; Fax: 631-632-1992; e-mail: basil.rigas{at}stonybrook.edu

The inhibitory effect of NO-donating aspirin (NO-ASA) on colon cancer has been demonstrated in vivo and in vitro but its mechanism is still obscure. We investigated the effect of NO-ASA on angiogenesis. Four groups of athymic mice (N = 12) bearing subcutaneous xenotransplants of HT-29 human colon cancer cells were injected intratumorally twice a week for three weeks with vehicle or meta NO-ASA or para NO-ASA; the fourth group received no injections. The necrotic area of tumors, expressed as % of total area, was similar in the non-injected and vehicle-injected groups (51.8 ± 2.8 vs. 52.2± 4.1; P>0.05; mean± SEM for these and subsequent values). Compared to the vehicle group, the necrotic area of tumors was higher in the m-NO-ASA (61.0 ± 2.7, p < 0.02) and p-NO-ASA (65.8 ± 2.4, p < 0.001) treated groups. NO-ASA decreased microvessel density: vehicle = 11.7± 0.8; m-NO-ASA = 7.8±0.6 (P = 0.0003 vs. vehicle); p-NO-ASA 6.2±0.7 (P = 0.0001 vs. vehicle). The expression of VGEF was significantly reduced in response to NO-ASA, with the p- isomer being more potent than the m-. NO-ASA altered the spatial distribution of VGEF expression, with 16.7% of the vehicle-treated xenografts displaying diminished VEGF in the inner region of the area between necrosis and the outer perimeter of the tumor, compared to those treated with m- (58.3%) or p-NO-ASA (75%; p<0.01 for both vs. control). Our findings indicate that NO-ASA suppresses the expression of VEGF, which leads to suppressed angiogenesis. The antiangiogenic activity of NO-ASA may be part of its antineoplastic effect.

Key Words: NO-aspirin • colon cancer • chemoprevention • NO-NSAIDs • angiogenesis • VEGF

Received December 17, 2007; revised April 25, 2008; accepted May 17, 2008.


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