P-type proton pumps are a large, ubiquitous and varied family of membrane proteins that are involved in many transport processes in virtually all living organisms, of which specialized form of pump exist in parietal cells in stomach. Proton pump inhibitors (PPI) are the standard of treatment for acid-related diseases based on potent inhibition of gastric acid secretion through the blocking of H+ efflux. Based on our previous report (Clin Cancer Res 10:8687-96, 2004) that pantoprazole, one of PPIs, can induce selective apoptosis in gastric cancer cells, and exert significant anti-cancer effects in xenograft models, we hypothesized there might be other potential mechanisms of pantoprazole for anticancer effects in addition to selective induction of apoptosis. In in vitro model of Helicobacter pylori or indomethacin-induced gastric mucosal cell damages, we measured the influence of pantoprazole on in vitro angiogenesis, changes of angiogenic growth factors, and changes of inflammatory mediators or cytoprotective proteins with in vitro angiogenesis assay and western blots. H. pylori infection was associated with significant levels of angiogenesis reflected with increase CD31 expression and IL-8 in infected gastric mucosa and increased expressions of COX-2, HIF-1α, and VEGF. Pantoprazole decreased these angiogenic events after H. pylori infection significantly. In addition to these anti-angiogenic activities, pantoprazole significantly induced HO-1 expression in a dose dependent manner. Marked increases in inflammatory mediators after indomethacin treatment were significantly attenuated in parallel with HO-1 induction after pantoprazole treatment, suggesting that overt anti-inflammatory activities were operated with PPI. Taken together, pantoprazole can be applied as chemopreventive purpose based on significant anti-angiogenic acitivities and anti-inflammatory actions, that is, the novel indication of PPI far beyond the acid suppression.
Second AACR Centennial Conference on Translational Cancer Medicine-- July 20-23, 2008; Monterey, CA