title: Tumour growth inhibition and anti-angiogenic effects using curcumin correspond to combined PDE2 and PDE4 inhibition.
abstract: Vascular endothelial growth factor (VEGF) plays a major role in angiogenesis by stimulating endothelial cells. Increase in cyclic AMP (cAMP) level inhibits VEGF-induced endothelial cell proliferation and migration. Cyclic nucleotide phosphodiesterases (PDEs), which specifically hydrolyse cyclic nucleotides, are critical in the regulation of this signal transduction. We have previously reported that PDE2 and PDE4 up-regulations in human umbilical vein endothelial cells (HUVECs) are implicated in VEGF-induced angiogenesis and that inhibition of PDE2 and PDE4 activities prevents the development of the in vitro angiogenesis by increasing cAMP level, as well as the in vivo chicken embryo angiogenesis. We have also shown that polyphenols are able to inhibit PDEs. The curcumin having anti-cancer properties, the present study investigated whether PDE2 and PDE4 inhibitors and curcumin could have similar in vivo anti-tumour properties and whether the anti-angiogenic effects of curcumin are mediated by PDEs. Both PDE2/PDE4 inhibitor association and curcumin significantly inhibited in vivo tumour growth in C57BL/6N mice. In vitro, curcumin inhibited basal and VEGF-stimulated HUVEC proliferation and migration and delayed cell cycle progression at G0/G1, similarly to the combination of selective PDE2 and PDE4 inhibitors. cAMP levels in HUVECs were significantly increased by curcumin, similarly to rolipram (PDE4 inhibitor) and BAY-60-550 (PDE2 inhibitor) association, indicating cAMP-PDE inhibitions. Moreover, curcumin was able to inhibit VEGF-induced cAMP-PDE activity without acting on cGMP-PDE activity and to modulate PDE2 and PDE4 expressions in HUVECs. The present results suggest that curcumin exerts its in vitro anti-angiogenic and in vivo anti-tumour properties through combined PDE2 and PDE4 inhibition.
authors.forename: Abdurazzag
authors.initials: A
authors.lastname: Abusnina
authors.forename: Thérèse
authors.initials: T
authors.lastname: Keravis
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Zhou
authors.forename: Hélène
authors.initials: H
authors.lastname: Justiniano
authors.forename: Annelise
authors.initials: A
authors.lastname: Lobstein
authors.affiliation: Dr. Claire Lugnier, Université de Strasbourg, CNRS UMR 7213, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, 74 route du Rhin, CS 60024, 67401 Illkirch, France, Tel.: +33 3 68 85 41 01, Fax: +33 3 68 85 43 13, E-mail: claire.lugnier@unistra.fr.
authors.forename: Claire
authors.initials: C
authors.lastname: Lugnier
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry*; D000818:Animals; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D003474:Curcumin / Q000737:chemistry*; D000242:Cyclic AMP / Q000378:metabolism; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000037:antagonists & inhibitors*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D008297:Male; D008545:Melanoma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D058988:Phosphodiesterase 4 Inhibitors / Q000737:chemistry*; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry*; D020889:Rolipram / Q000737:chemistry; D014227:Triazines / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing
chemical_list: C539142:2-(3,4-dimethoxybenzyl)-7-(1-(1-hydroxyethyl)-4-phenylbutyl)-5-methylimidazo(5,1-f)(1,2,4)triazin-4 (3H)-one; D020533:Angiogenesis Inhibitors; D007093:Imidazoles; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D014227:Triazines; D042461:Vascular Endothelial Growth Factor A; D000242:Cyclic AMP; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; C517275:PDE2A protein, human; D003474:Curcumin; D020889:Rolipram
keywords: Cyclic AMP; HUVEC; VEGF; melanoma cell; tumour growth