The Amaryllidaceae alkaloid narciclasine as modulator of endothelial activation processes

Narciclasine is an isocarbostyril alkaloid that was first isolated from Narcissus species (Amaryllidaceae) more than 50 years ago. In the last decades, narciclasine attracted huge attention due to its high potency as anti-tumor compound. However, beyond cancer research, knowledge on the pharmacological activity of narciclasine is largely lacking. Only few studies reported about an anti-inflammatory potential of the alkaloid. Since both solid tumor growth and inflammation strongly depend on activation processes of vascular endothelial cells (ECs), we hypothesized that narciclasine might interfere with signaling pathways that regulate two crucial pathophysiological functions of ECs: the formation of new blood vessels (angiogenesis) and the interaction of leukocytes with ECs (extravasation and tissue infiltration). Indeed, by using a battery of both in vitro and in vivo models, we showed that narciclasine strongly inhibits angiogenic processes as well as leukocyte-endothelial cell interaction. Most interestingly, we were able to elucidate the molecular mechanisms involved in these pharmacological activities: In human ECs, narciclasine blocked de novo protein biosynthesis by approx. 50% without inducing considerable cytotoxicity. This led to a loss of the short-lived cell membrane proteins tumor necrosis factor receptor 1 (TNFR1) and vascular endothelial growth factor receptor 2 (VEGFR2), which explains the observed inhibitory actions of narciclasine on several major signaling events in ECs. Taken together, our investigations highlight the Amaryllidaceae alkaloid narciclasine as an interesting anti-inflammatory and anti-angiogenic compound that is worth to be further evaluated in preclinical studies.