Curcumin inhibits VEGF-mediated angiogenesis in human intestinal microvascular endothelial cells through COX-2 and MAPK inhibition

Background: Angiogenesis, the growth of new blood vessels, is a critical homeostatic mechanism which regulates vascular populations in response to physiological requirements and pathophysiological demand, including chronic inflammation and cancer. The importance of angiogenesis in gastrointestinal chronic inflammation and cancer has been defined, as antiangiogenic therapy has demonstrated benefit in models of inflammatory bowel disease and colon cancer treatment. Curcumin is a natural product undergoing evaluation for the treatment of chronic inflammation, including inflammatory bowel disease ( IBD). The effect of curcumin on human intestinal angiogenesis is not defined. Methods: The antiangiogenic effect of curcumin on in vitro angiogenesis was examined using primary cultures of human intestinal microvascular endothelial cells ( HIMECs), stimulated with vascular endothelial growth factor ( VEGF). Results: Curcumin inhibited proliferation, cell migration and tube formation in HIMECs induced by VEGF. Activation of HIMECs by VEGF resulted in enhanced expression of cyclo-oxygenase-2 ( COX-2) mRNA, protein and prostaglandin E-2 ( PGE(2)) production. Pretreatment of HIMECs with 10 mu M curcumin as well as 1 mu M NS398, a selective inhibitor of COX-2, resulted in inhibition of COX-2 at the mRNA and protein level and PGE2 production. Similarly COX-2 expression in HIMECs was significantly inhibited by Jun N-terminal kinase ( JNK; SP600125) and p38 mitogen-activated protein kinase ( MAPK; SB203580) inhibitors and was reduced by p44/42 MAPK inhibitor ( PD098059). Conclusions: Taken together, these data demonstrate an important role for COX-2 in the regulation of angiogenesis in HIMECs via MAPKs. Moreover, curcumin inhibits microvascular endothelial cell angiogenesis through inhibition of COX-2 expression and PGE2 production, suggesting that this natural product possesses antiangiogenic properties, which warrants further investigation as adjuvant treatment of IBD and cancer.