Insights into the pharmacology of the isocarbostyril alkaloid narciclasine – from anti-cancer to anti-inflammatory actions

Plants of the Amaryllidaceae family are known to contain numerous bioactive alkaloids. One prominent example is the isocarbostyril alkaloid narciclasine. In the last decades, narciclasine has been extensively investigated due to its anti-tumor effects. Interestingly, however, the actions of the compound on endothelial cells have not been analyzed so far. The endothelium crucially participates in the progression of pathologies such as cancer (angiogenesis) and inflammation (leukocyte extravasation). Thus, our group aims to characterize the action of narciclasine both in vivo and in vitro in the context of inflammation and cancer. As a source of narciclasine, we use an extract of the plant Haemanthus coccineus, which is adjusted to a content of 2.2% narciclasine. In addition, also the isolated compound was utilized.

Regarding the plant extract, only the non-basic main alkaloid narciclasine was able to exert anti-inflammatory actions, whereas all basic alkaloids present in H. coccineus were inactive. Narciclasine effectively addressed the pro-inflammatory activation process of endothelial cells, since it inhibited the extravasation of leukocytes through the endothelial barrier into the inflamed tissue. Besides endothelial cells, narciclasine also limited the activation of leukocytes. Insights into the underlying mechanisms revealed that the alkaloid blocks NFκB-dependent gene expression, but does not influence the canonical activation cascade of this pro-inflammatory transcription factor. In the context of cancer, we found that narciclasine affects key features of tumor angiogenesis: The compound blocked endothelial proliferation by inducing a G1/G0 arrest, inhibited undirected as well as directed endothelial cell migration, and reduced endothelial tube formation on Matrigel.

In conclusion, narciclasine represents a versatile alkaloid with profound actions on activated endothelial cells. Thus, the compound might serve as a valuable lead structure to advance anti-inflammatory and anti-cancer drug discovery.

Acknowledgements: This research is in part supported by the Else Kröner-Fresenius Foundation (EKFS), Research Training Group Translational Research Innovation – Pharma (TRIP).

Keywords: narciclasine, inflammation, angiogenesis, endothelium.