Dimethylfumarate Inhibits Angiogenesis In Vitro and In Vivo: A Possible Role for Its Antipsoriatic Effect?

Abstract

The fumaric acid esters (FAEs) have been used for the oral treatment of psoriasis for some 50 years. Given that a persistent and maintained angiogenesis is associated with several cutaneous diseases, including psoriasis, we sought in our study to gain further insight into their mechanism of action by investigating whether FAEs are able to interfere with angiogenesis mechanisms. Our results demonstrate that dimethylfumarate (DMF) inhibits certain functions of endothelial cells, namely, differentiation, proliferation, and migration. This activity was not exhibited by similar concentrations of monomethylfumarate or fumaric acid. Our data indicate that DMF inhibits the growth of transformed and nontransformed cells in a dose-dependent manner. The growth-inhibitory effect exerted by this compound on proliferating endothelial cells could be due, at least in part, to an induction of apoptosis. Inhibition by DMF of the mentioned essential steps of in vitro angiogenesis is consistent with the observed inhibition of in vivo angiogenesis, substantiated using chick chorioallantoic membrane and live fluorescent zebrafish embryo neovascularization assays. The antiangiogenic activity of DMF may contribute to the antipsoriatic, antitumoral, and antimetastatic activities of this compound and suggests its potential in the treatment of angiogenesis-related malignancies.

The Antipsoriatic Agent Monomethylfumarate Has Antiproliferative, Prodifferentiative, and Anti-Inflammatory Effects on Keratinocytes

“…These effects seem to account, at least in part, for its action as an antipsoriatic agent. These findings, in addition to previously published data, suggest that MMF is exerting inhibitory functions on the three major cell types involved in the pathogenesis of psoriasis (keratinocytes, immune cells, and endothelial cells) (Nibbering et al, 1993;García-Caballero et al, 2011). Together with the clinical data obtained for the antipsoriatic drug Fumaderm (Mrowietz et al, 1998;Rostami Yazdi and Mrowietz, 2008), used in Germany since 1994, these results suggest that MMF may be an ideal therapy for treating moderate to severe psoriasis.…”

“…Thus, MMF has known effects on immune cells, such as dendritic cells and granulocytes, which could possibly account in part for its antipsoriatic actions (Nibbering et al, 1993;Litjens et al, 2004b). In addition, FAEs (including MMF) exhibit inhibitory effects on the proliferation, differentiation, migration, and tube formation of endothelial cells (Arbiser, 2011;García-Caballero et al, 2011). However, the known effects of MMF on immune cells and endothelial cells may not adequately explain the superior results with Fumaderm in treating moderate to severe psoriasis, and which are accompanied by limited and nonserious side effects compared with other immune system-targeting drugs, such as biologic drugs (Mrowietz et al, 1998;Menter et al, 2008).…”

Angiogénesis, metabolismo y enfermedad

“…Así, fármacos diseñados para el tratamiento del cáncer de colon se emplean en la actualidad como terapia preferencial de la degeneración macular húmeda (10). Nuestro grupo publicó en la revista más relevante en el campo de la Dermatología que el dimetilfumarato, utilizado para el tratamiento de la psoriasis, presenta actividad antiangiogénica (11). También identificamos 180 enfermedades raras relacionadas con la angiogénesis (27 de las cuales, estrictamente angiogénicas) (12).…”

Screening of synergistic interactions of epigallocatechin-3-gallate with antiangiogenic and antitumor compounds

“…In the last years we have identified a number of natural compounds as new inhibitors of angiogenesis [see for instance [9][10][11][12][13][14]. We have also claimed for the need of combinatorial approaches to manage angiogenesis [5].…”