A new horizon for the steroidal alkaloid cyclovirobuxine D (huangyangning) and analogues: Anticancer activities and mechanism of action

Abstract

Abstract The steroidal alkaloid cyclovirobuxine D (Cvb-D) is the active principle of the oral drug huangyangning used for many years in China for the treatment of cardiovascular and cerebrovascular diseases. The drug is listed in the Chinese pharmacopeia. Recent studies have revealed that this unsung alkaloid also displays anticancer properties in vitro and in vivo. The drug activates several signaling pathways, and notably represses phosphorylation of proteins EGFR, ERK, Akt, mTOR. Thereby, Cvb-D exerts antiproliferative and antimetastatic activities. In the present review, the anticancer effects of Cvb-D and related natural products isolated from Buxus species have been analyzed. The molecular targets of Cvb-D are unknown at present, but hypotheses are formulated based on the signaling pathways modulated by the drug and the analogy with other compounds. Proteins EGFR and CTHRC1, implicated in the antiproliferative action of Cvb-D, could be considered as upstream targets. A bolder assumption is also formulated with the metastasis-associated protein S100A4 as a potential co-target for Cvb-D. This review aims to shed light on the anticancer properties of Cvb-D and to encourage further mechanistic studies with this drug with a good safety profile and a recognized anti-cardiovascular efficacy.