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

Abstract

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 E2 (PGE2) production. Pretreatment of HIMECs with 10 μM curcumin as well as 1 μM 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.

Activation of ATM/Chk1 by curcumin causes cell cycle arrest and apoptosis in human pancreatic cancer cells

“…Inhibition of cell growth and induction of apoptosis is the common mechanism by which curcumin shows its anticancer effects. Accumulating evidence suggests the involvement of multiple-signaling pathways by which curcumin causes growth suppression of human cancer cells (Cheng et al, 2001;Hidaka et al, 2002;Bharti et al, 2003;Kim et al, 2003;Shishodia et al, 2003;Blasius et al, 2006;Lev-Ari et al, 2006;Mitra et al, 2006;Park et al, 2006;Tan et al, 2006;Aggarwal et al, 2007;Aoki et al, 2007;Deeb et al, 2007;Fahey et al, 2007;Lin et al, 2007Lin et al, , 2008Marín et al, 2007;Shankar and Srivastava, 2007;Srivastava et al, 2007;Weir et al, 2007;Binion et al, 2008;Freudlsperger et al, 2008;Ji et al, 2008;Kasinski et al, 2008;Mackenzie et al, 2008;Shankar et al, 2008;Sun et al, 2008). Phase I clinical trials of curcumin demonstrated encouraging chemopreventive effects in patients with high-risk or pre-malignant lesions.…”

Molecular characterization, tissue expression profile, and single nucleotide polymorphism analysis of the periostin gene in swine

“…Furthermore, experiments have shown that periostin mRNA expression increased significantly in rat pulmonary artery smooth muscle cells under a hypoxic stress response, which is similar to the process that occurs during atherosclerosis (Li et al, 2004). The results of other studies have shown that periostin can regulate breast cancer cells and the expression of kinase domain receptor in human capillary endothelial cells (Försti et al, 2007;Binion et al, 2008). Transforming growth factor-beta 1 (TGFb1) was found to induce periostin production, and this finding has been confirmed in colon cancer cells (Tai et al, 2005).…”

Down-Regulation of MutS Homolog 2 (MSH2) Expression by Curcumin Enhances Cytotoxicity Induced by Gemcitabine in Human Lung Adenocarcinoma Cells

“…**P<0.01 using Student's t-test for comparison of cells treated with curcumin and gemcitabine in SB202190 and DMSO-pretreated cells. significantly suppressed by curcumin pretreatment in human intestinal microvascular endothelial cells (HIMECs), and curcumin could attenuate VEGF-induced cyclo-oxygenase-2 (COX-2) expression through inhibition of MAPK pathway [24]. Previous results have indicated that curcumin induces cell apoptosis through p38 MAPKdependent up-regulation of FasL in human hepatocellular carcinoma cells [25].…”