NSAID inhibition of GI cancer growth: clinical implications and molecular mechanisms of action.

Epidemiological studies suggest that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) reduce the incidence of and mortality from colorectal, gastric, and esophageal cancers. The precise mechanisms by which NSAIDs exert their chemopreventive effects are not fully explained, but likely involve inhibition of cyclo-oxygenase, the enzyme that converts arachidonic acid to prostaglandins. Two isoforms of this enzyme, cyclo-oxygenase 1 (COX-1) and COX-2, have been identified. COX-2 is absent in normal mucosa but is overexpressed in colonic, gastric, and esophageal cancers, as well as their precursor lesions. The inhibition of COX-2 through either pharmacological agents or gene deletion results in suppression of colonic polyp formation. NSAIDs reduce colonic, gastric, and esophageal cancer cell growth, in part, by inducing apoptosis. However, the antineoplastic effects of NSAIDs may be partly independent of their ability to inhibit COX-2. The mechanisms involved in the antineoplastic actions of NSAIDs include inhibition of angiogenesis (essential for delivery of oxygen and nutrients to a growing tumor), induction of apoptosis (which is usually reduced in cancer cells) by stimulation of proapoptotic genes, and direct inhibition of cancer cell growth by blocking signal transduction pathways responsible for cell proliferation.

von Hippel Lindau tumor suppressor and HIF-1alpha: new targets of NSAIDs inhibition of hypoxia-induced angiogenesis.

Nonsteroidal anti-inflammatory drugs (NSAIDs) block prostaglandin synthesis and impair healing of gastrointestinal ulcers and growth of colonic tumors, in part, by inhibiting angiogenesis. The mechanisms of this inhibition are incompletely explained. Here we demonstrate that both nonselective (indomethacin) and COX-2-selective (NS-398) NSAIDs inhibit hypoxia-induced in vitro angiogenesis in gastric microvascular endothelial cells via coordinated sequential events: 1) increased expression of the von Hippel-Lindau (VHL) tumor suppressor, which targets proteins for ubiquitination leading to 2) reduced accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) and, as a result, 3) reduced expression of vascular endothelial growth factor (VEGF) and its specific receptor Flt-1. Because HIF-1alpha is the major trigger for hypoxia-induced activation of the VEGF and Flt-1 genes, this could explain how NSAIDs inhibit hypoxia-induced angiogenesis. Exogenous VEGF and, to a lesser extent, exogenous prostaglandins partly reversed the NSAIDs inhibition of hypoxia-induced angiogenesis. Taken together, these results indicate that NSAIDs inhibit hypoxia-induced angiogenesis in endothelial cells by inhibiting VEGF and Flt-1 expression through increased VHL expression and the resulting ubiquitination and degradation of HIF-1alpha. This action of NSAIDs has both prostaglandin-dependent and prostaglandin-independent components.