Abusnina Abdurazzag, Keravis Thérèse, Zhou Qingwei, Justiniano Hélène, Lobstein Annelise, Lugnier Claire
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:
Thromb Haemost. 2015 Feb;113(2):319-28. doi: 10.1160/TH14-05-0454. Epub 2014 Sep 18.
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.
血管内皮生长因子（VEGF）通过刺激内皮细胞在血管生成中起主要作用。环磷酸腺苷（cAMP）水平的升高会抑制VEGF诱导的内皮细胞增殖和迁移。特异性水解环核苷酸的环核苷酸磷酸二酯酶（PDEs）在这种信号转导的调节中起关键作用。我们之前报道过，人脐静脉内皮细胞（HUVECs）中PDE2和PDE4的上调与VEGF诱导的血管生成有关，并且抑制PDE2和PDE4的活性可通过提高cAMP水平来阻止体外血管生成以及体内鸡胚血管生成。我们还表明多酚能够抑制PDEs。姜黄素具有抗癌特性，本研究调查了PDE2和PDE4抑制剂以及姜黄素是否具有相似的体内抗肿瘤特性，以及姜黄素的抗血管生成作用是否由PDEs介导。PDE2/PDE4抑制剂组合和姜黄素均显著抑制了C57BL/6N小鼠体内的肿瘤生长。在体外，姜黄素抑制基础状态和VEGF刺激的HUVEC增殖与迁移，并使细胞周期在G0/G1期的进程延迟，这与选择性PDE2和PDE4抑制剂的组合相似。与罗匹尼罗（PDE4抑制剂）和BAY - 60 - 550（PDE2抑制剂）组合相似，姜黄素显著提高了HUVECs中的cAMP水平，表明其对cAMP - PDE有抑制作用。此外，姜黄素能够抑制VEGF诱导的cAMP - PDE活性而不影响cGMP - PDE活性，并调节HUVECs中PDE2和PDE4的表达。目前的结果表明，姜黄素通过联合抑制PDE2和PDE4发挥其体外抗血管生成和体内抗肿瘤特性。
