Nitro-aspirin inhibits MCF-7 breast cancer cell growth: Effects on COX-2 expression and Wnt/β-catenin/TCF-4 signaling

There is current evidence implicating the Wnt/beta Phi-catenin/TCF pathway in breast cancer. We investigated the effect of para- and meta-positional isomers of nitric oxide-releasing aspirin (NO-ASA), and aspirin (ASA) on MCF-7 human breast cancer cell growth and beta-catenin/TCF signaling. The p- and m-NO-ASA isomers strongly inhibited cell growth and beta-catenin/TCF transcriptional activity compared to ASA; the IC(50)s for growth inhibition were 57 4, 193 10 and >5000 mu M, and for transcriptional inhibition they were 12 +/- 1.8, 75 +/- 6.5 and >5000 mu M for p-, m-NO-ASA and ASA. respectively. p-NO-ASA reduced the expression of Wnt/beta-catenin downstream target gene cyclin D1, and total cellular P-catenin levels. COX-2 expression was induced by p-NO-ASA, protein kinase C inhibitors reversed this induction. p-NO-ASA blocked the cell cycle transition at S to G(2)/M phase. These studies suggest a targeted chemopreventive/chemotherapeutic potential for NO-ASA against breast cancer. (C) 2009 Elsevier Inc. All rights reserved.