CAPE suppresses VEGFR-2 activation, and tumor neovascularization and growth

Abstract

The growth and metastasis of human solid tumors and the development of conditions such as diabetic retinopathy, rheumatoid arthritis, inflammatory psoriasis, and others are regulated by the balance between angiogenic stimulators and inhibitors released in the angiogenic-pathological microenvironment. Vascular endothelial growth factor (VEGF), an angiogenic factor, is a potent endothelial-specific mitogen that activates endothelial cells in pathological angiogenesis. Recently, we demonstrated that caffeic acid phenethyl ester (CAPE) inhibits tumor growth, invasion, and metastasis. However, the precise molecular mechanism underlying the inhibitory effect of CAPE on VEGF-mediated angiogenesis remains unknown. Here, we show that CAPE suppressed VEGF-induced proliferation, tube formation, migration, the formation of actin stress fibers and loss of VE-cadherin at cell-cell contacts in endothelial cells, indicating the inhibition of VEGF-mediated VEGF receptor-2 (VEGFR-2) and its downstream signal activation in vitro. CAPE blocked VEGF-stimulated neovascularization in the Matrigel plugs assay, and reduced vascular permeability in mouse skin capillaries in vivo. CAPE inhibited the growth and neovascularization of primary tumor cells in C57BL/6 and BALB/c mice inoculated with Lewis lung carcinoma, colon carcinoma, and melanoma cells. These results suggest that CAPE negatively modulates VEGF-induced angiogenesis by suppressing VEGFR-2 activation, and might be a therapeutic avenue for anti-angiogenesis.

Caffeic Acid Phenethyl Ester (CAPE) Induces VEGF Expression and Production in Rat Odontoblastic Cells

“…e cytotoxicity of CAPE in the range of 10 μg/ml concentration on odontoblast-like cells, KN-3 cells, was not observed. Consistent with the present observation, previous reports demonstrated that CAPE had no cytotoxicity for human umbilical vein endothelial cells (HUVEC) in almost the same concentration as our study [27,28]. is finding suggests that the concentration of CAPE used in the present study could be clinically applied as a reasonable dose.…”

Wu-Tou Decoction in Rheumatoid Arthritis: Integrating Network Pharmacology and In Vivo Pharmacological Evaluation

“…Moreover, it has been reported that glycyrrhetinic acid could not only potentiate the therapeutic effects but could also decrease the adverse effects of NSAIDs or DMARDs during treatment course of RA (Huang et al, 2016). Phenethylcaffeate, one of the active components of Ephedrae Herba ( Ephedra sinica Stapf), exert multiple pharmacological effects, including anti-inflammation, immunomodulation (Armutcu et al, 2015; Li et al, 2017), regulation of VEGF-induced angiogenesis (Chung et al, 2013), inhibition of leukotrienes biosynthesis (Boudreau et al, 2012), and so on. All of these studies indicated that glycyrrhetinic acid and phenethylcaffeate might be served as additives to RA treatment.…”

Plants and Natural Products for the Treatment of Skin Hyperpigmentation – A Review

“…Caffeic acid phenethyl ester (11) occurs naturally in plants and propolis, and it is bioactivated by TYR, generating derivatives that are cytotoxic to melanoma cells. In B16F10 melanoma cells, it potently suppresses tumor growth and neovascularization by preventing VEGFR-2 activation [11].…”

“…Caffeic acid phenethyl ester (11) occurs naturally in plants and propolis, and it is bioactivated by TYR, generating derivatives that are cytotoxic to melanoma cells. In B16F10 melanoma cells, it potently suppresses tumor growth and neovascularization by preventing VEGFR-2 activation [11]. Caffeic acid phenethyl ester also effectively slows α-MSH-stimulated melanin synthesis by suppressing TYR, TRP-1, TRP-2, and MITF expression [12].…”