Cepharanthine: An update of its mode of action, pharmacological properties and medical applications

Abstract

Background: Cepharanthine (CEP) is a drug used in Japan since the 1950s to treat a number of acute and chronic diseases, including treatment of leukopenia, snake bites, xerostomia and alopecia. It is the only approved drug for Human use in the large class of bisbenzylisoquinoline alkaloids. This natural product, mainly isolated from the plant Stephania cephalantha Hayata, exhibits multiple pharmacological properties including anti-oxidative, anti-inflammatory, immuno-regulatory, anti-cancer, anti-viral and anti-parasitic properties.

Purpose: The mechanism of action of CEP is multifactorial. The drug exerts membrane effects (modulation of efflux pumps, membrane rigidification) as well as different intracellular and nuclear effects. CEP interferes with several metabolic axes, primarily with the AMP-activated protein kinase (AMPK) and NFκB signaling pathways. In particular, the anti-inflammatory effects of CEP rely on AMPK activation and NFκB inhibition.

Conclusion: In this review, the historical discovery and development of CEP are retraced, and the key mediators involved in its mode of action are presented. The past, present, and future of CEP are recapitulated. This review also suggests new opportunities to extend the clinical applications of this well-tolerated old Japanese drug.

Keywords: Alkaloids; Cancer; Cepharanthine; Inflammation; Natural products; Stephania.

Graphical abstract

Fig. 1

Chemical structure and conformation of cepharanthine (C₃₇H₃₈N₂O₆).

Fig. 2

(a) Stephania japonica JB Koishikawa, photo of the plant leaves (Japan, 2018). (b) The caudex of Stephania rotunda (Pierre Fabre Botanical Institute, Cambounet-sur-Sor, France). (c and d) Stephania cephalantha Hayata (China), from the Paris Herbarium, at the National Museum of Natural History, Paris, France (http://coldb.mnhn.fr/catalognumber/mnhn/p/p02467444 and p02384134).

Fig. 3

History of CEP discovery and development. Eighty years of evolution of CEP, to mention its main clinical applications and biochemical properties.

Fig. 4

Structure of six bisbenzylisoquinoline (BBIQ) derivatives.

Fig. 5

Pharmaceutical sales of CEP for years 2014–18 (from IMS Health, now IQVIA). The graph shows both the annual sales in k€ (left axis) and in k-units (right axis). Numbers for year 2018 are estimates based on the June 2018 MTA (Moving Annual Total) data.

Fig. 6

Main signaling pathways and sites of action of CEP in cells. The multifaceted mechanism of action of CEP leads to several clinical applications (treatment of snake bites, alopecia aerata, xerostomia, leukopenia). Other potential applications of CEP are also explored for the treatment of cancer, osteoporosis, virus and parasites infections, sepsis and chronic inflammatory diseases.