Tumour growth inhibition and anti-angiogenic effects using curcumin correspond to combined PDE2 and PDE4 inhibition

Abdurazzag Abusnina; Thérèse Keravis; Qingwei Zhou; Hélène Justiniano; Annelise Lobstein; Claire Lugnier

doi:10.1160/TH14-05-0454

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2015; 113(02): 319-328
DOI: 10.1160/TH14-05-0454

Endothelium and Angiogenesis

Schattauer GmbH

Tumour growth inhibition and anti-angiogenic effects using curcumin correspond to combined PDE2 and PDE4 inhibition

Abdurazzag Abusnina

¹CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France

³Present address: Department of pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Tripoli, Libya

,

Thérèse Keravis

¹CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France

,

Qingwei Zhou

¹CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France

⁴Present address: Department of Biochemistry and Molecular Biology, Regenerative Medical Sciences Institute, Jilin University, Chang Chun, Jilin, P. R. of China

,

Hélène Justiniano

¹CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France

,

Annelise Lobstein

²CNRS UMR 7200 Laboratoire d’Innovation Thérapeutique, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France

,

Claire Lugnier

¹CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France

› Author Affiliations

Abstract

Summary

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 antitumour properties through combined PDE2 and PDE4 inhibition.

Keywords

Cyclic AMP - HUVEC - melanoma cell - VEGF - tumour growth

Full Text

References

References
1 Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other diseases. Nat Med 1995; 01: 27-31.
2 Griffioen AW, Molema G. Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. Pharmacol Rev 2000; 52: 237-268.
3 Granci V, Dupertuis YM, Pichard C. Angiogenesis as a potential target of phar-maconutrients in cancer therapy. Cur Opin Clin Nutr Metab Care 2010; 13: 417-422.
4 Ammon HP, Wahl MA. Pharmacology of Curcuma longa. Planta Med 1991; 57: 1-7.
5 Kunnumakkara AB, Anand P, Aggarwal BB. Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signalling proteins. Cancer Lett 2008; 269: 199-225.
6 Zhou H, Beevers CS, Huang S. The targets of curcumin. Curr Drug Targets 2011; 12: 332-347.
7 Bengmark S, Mesa MD, Gil A. Plant-derived health: the effects of turmeric and curcuminoids. Nutr Hosp 2009; 24: 273-281.
8 Huang MT, Lou YR, Ma W. et al. Inhibitory effects of dietary curcumin on fore-stomach, duodenal, and colon carcinogenesis in mice. Cancer Res 1994; 54: 5841-5847.
9 Arbiser JL, Klauber N, Rohan R. et al. Curcumin is an in vivo inhibitor of angio-genesis. Mol Med 1998; 04: 376-383.
10 Schoeffter P, Lugnier C, Demesy-Waeldele F. et al. Role of cyclic AMP- and cyclic GMP-phosphodiesterases in the control of cyclic nucleotide levels and smooth muscle tone in rat isolated aorta. A study with selective inhibitors. Bio-chem Pharmacol 1987; 36: 3965-3972.
11 Houslay MD, Conti M, Francis SH. The cyclic nucleotides. Handb Exp Pharmacol 2011; 204: v-vii.
12 Morgado M, Cairräo E, Santos-Silva AJ, Verde I. Cyclic nucleotide-dependent relaxation pathways in vascular smooth muscle. Cell Mol Life Sci 2012; 69: 247-266.
13 Lugnier C. Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol Ther 2006; 109: 366-398.
14 Omori K, Kotera J. Overview of PDEs and their regulation. Circ Res 2007; 100: 309-327.
15 Francis SH, Blount MA, Corbin JD. Mammalian cyclic nucleotide phosphodies-terases: molecular mechanisms and physiological functions. Physiol Rev 2011; 91: 651-690.
16 Keravis T, Lugnier C. Cyclic nucleotide phosphodiesterase (PDE) isozymes as targets of the intracellular signalling network: benefits of PDE inhibitors in various diseases and perspectives for future therapeutic developments. Br J Pharmacol 2012; 165: 1288-1305.
17 Favot L, Keravis T, Lugnier C. VEGF-induced HUVEC migration and proliferation are decreased by PDE2 and PDE4 inhibitors. Thromb Haemost 2003; 90: 334-343.
18 Favot L, Keravis T, Holl V. et al. Modulation of VEGF-induced endothelial cell cycle protein expression through cyclic AMP hydrolysis by PDE2 and PDE4. Thromb Haemost 2004; 92: 634-645.
19 Abusnina A, Keravis T, Yougbaré I. et al. Anti-proliferative effect of curcumin on melanoma cells is mediated by PDE1A inhibition that regulates the epigen-etic integrator UHRF1. Mol Nutr Food Res 2011; 55: 1677-1689.
20 Marivet MC, Bourguignon JJ, Lugnier C. et al. Inhibition of cyclic adeno-sine-3‘, 5‘-monophosphate phosphodiesterase from vascular smooth muscle by rolipram analogues. J Med Chem 1989; 32: 1450-1457.
21 Podzuweit T, Nennstiel P, Müller A. Isozyme selective inhibition of cGMP-stimulated cyclic nucleotide phosphodiesterases by erythro-9-(2-hydroxy-3-nonyl) adenine. Cell Signal 1995; 07: 733-738.
22 Raeburn D, Underwood L, Lewis A. et al. Anti-inflammatory and bronchodilator properties of RP 73401, a novel and selective phosphodiesterase type IV inhibitor. Br J Pharmacol 1994; 113: 1423-1431.
23 Boess FG, Hendrix M, van der Staay FJ. et al. Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance. Neur-opharmacology 2004; 47: 1081-1092.
24 Lugnier C, Schoeffter P, Le Bec A. et al. Selective inhibition of cyclic nucleotide phosphdiesterases of human, bovine and rat aorta. Biochem Pharmacol 1986; 35: 1743-1751.
25 Lowry OH, Rosebrough NJ, Farr AL. et al. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193: 265-275.
26 Keravis T, Thaseldar-Roumié R, Lugnier C. Assessment of phosphodiesterase isozyme contribution in cell and tissue extracts. Methods Mol Biol 2005; 307: 63-74.
27 Campos-Toimil M, Keravis T, Orallo F. et al. Short-term and long-term treatments with a phosphodiesterase-4 (PDE4) inhibitor result in opposing agonist-induced Ca2+ responses in endothelial cells. Br J Pharmacol 2008; 154: 82-92.
28 Keravis T, Silva AP, Favot L. et al. Role of PDEs in vascular healty and disease: endothelial PDEs and angiogenesis. In: Cyclic Nucleotide Phosphodiesterases in Health and Disease. CRC; 2006. pp. 417-439.
29 Lugnier C, Schini VB. Characterisation of cyclic nucleotide phosphodiesterases from cultured bovine aortic endothelial cells. Biochem Pharmacol 1990; 39: 75-84.
30 Souness JE, Diocee BK, Martin W. et al. Pig aortic endothelial-cell cyclic nucleo-tide phosphodiesterases. Use of phosphodiesterase inhibitors to evaluate their roles in regulating cyclic nucleotide levels in intact cells. Biochem J 1990; 266: 127-32.
31 Netherton SJ, Maurice DH. Vascular endothelial cell cyclic nucleotide phospho-diesterases and regulated cell migration: implications in angiogenesis. Mol Pharmacol 2005; 67: 263-272.
32 Favot L, Martin S, Keravis T. et al. Involvement of cyclin-dependent pathway in the inhibitory effect of delphinidin on angiogenesis. Cardiovasc Res 2003; 59: 479-487.
33 Alvarez E, Justiniano-Basaran H, Lugnier C. et al. Study of the mechanisms involved in the vasorelaxation induced by (-)-epigallocatechin-3-gallate in rat aorta. Br J Pharmacol 2006; 147: 269-280.
34 Yarwood SJ, Steele MR, Scotland G. et al. The RACK1 signalling scaffold protein selectively interacts with the cAMP-specific phosphodiesterase PDE4D5 isoform. J Biol Chem 1999; 274: 14909-14917.
35 Dodge KL, Khouangsathiene S, Kapiloff MS. et al. 2001. mAKAP assembles a protein kinase A/PDE4 phosphodiesterase cAMP signalling module. EMBO J 2001; 20: 1921-1930.
36 Brunton LL. PDE4: arrested at the border. Sci STKE 2003; 204: PE44.
37 Georget M, Mateo P, Vandecasteele G. et al. Cyclic AMP compartmentation due to increased cAMP-phosphodiesterase activity in transgenic mice with a cardiac-directed expression of the human adenylyl cyclase type 8 (AC8). FASEB J 2003; 17: 1380-1391.
38 Maurice DH. Subcellular signalling in the endothelium: cyclic nucleotides take their place. Curr Opin Pharmacol 2011; 11: 656-664.
39 Lugnier C, Keravis T, Le Bec A. et al. 1999. Characterisation of cyclic nucleotide phosphodiesterase isoforms associated to isolated cardiac nuclei. Biochim Bio-phys Acta 1999; 1472: 431-446.
40 Seybold J, Thomas D, Witzenrath M. et al. Tumour necrosis factor-alpha-dependent expression of phosphodiesterase 2: role in endothelial hyperpermeabil-ity. Blood 2005; 105: 3569-3576.
41 Rampersad SN, Ovens JD, Huston E. et al. Cyclic AMP phosphodiesterase 4D (PDE4D) Tethers EPAC1 in a vascular endothelial cadherin (VE-Cad)-based signalling complex and controls cAMP-mediated vascular permeability. J Biol Chem 2010; 285: 33614-33622.
42 Geoffroy V, Fouque F, Nivet V. et al. Activation of a cGMP-stimulated cAMP phosphodiesterase by protein kinase C in a liver Golgi-endosomal fraction. Eur J Biochem 1999; 259: 892-900.
43 Xu H, Czerwinski P, Hortmann M. et al. Protein kinase C alpha promotes angio-genic activity of human endothelial cells via induction of vascular endothelial growth factor. Cardiovasc Res 2008; 78: 349-355.
44 Diebold I, Djordjevic T, Petry A. et al. Phosphodiesterase 2 mediates redox-sen-sitive endothelial cell proliferation and angiogenesis by thrombin via Rac1 and NADPH oxidase 2. Circ Res 2009; 104: 1169-1177.