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.

Activation of β2-adrenergic receptor by (R,R′)-4′-methoxy-1-naphthylfenoterol inhibits proliferation and motility of melanoma cells

“…Inhibition of cAMP-specific PDEs sharply enhanced ( R,R ’)-MNF’s ability to reduce the invasive potential of UACC-647 cells, which indicates the importance of maintaining elevated levels of cAMP in the suppression of melanoma cell motility. These findings are supported by other studies illustrating that inhibition of various members of the PDE family reduces motility of melanoma cells [26, 27, 50]. Recently, a novel class of molecules composed of two moieties, β 2 -AR-agonist pharmacophore and PDE4-inhibitor pharmacophore, was synthetized [51, 52].…”

Loss of phosphodiesterase 4D mediates acquired triapine resistance via Epac-Rap1-Integrin signaling

“…With regard to pro-tumorigenic activities, PDE4 inhibitors were reported to inhibit proliferation, migration, and progression of several solid tumors as well as hematological malignancies probably via cAMP-PKA signaling [35-38]. Accordingly, the cancer-preventive and therapeutic effects of several natural products including curcumin and resveratrol were attributed to PDE4D inhibition [39, 40]. Furthermore, there is strong evidence for PDE4 to promote angiogenesis via hypoxia-inducible factor in lung cancer [41].…”

Bioactive Compounds: Natural Defense Against Cancer?

“…Curcumin exerts anticancer effects through several mechanisms, which affect regulation of cell growth and apoptosis. For instance, curcumin can inhibit angiogenesis [76] as well as inhibit their proliferation and metastasis [77], decrease chronic inflammation [78] and combat mutated cancer cells [77]. Bisdemethoxycurcumin showed excellent inhibitory effects with an IC 50 value of 23.0 µM whilst the D 2 analog showed potent inhibitory effects at 8.2 µM [79].…”