Artemisinin (Qinghaosu) is a sesquiterpene lactone containing a 1,2,4-trioxane motif extracted from the medicinal plant species wormwood (Artemisia annua L.). It has been widely used for the treatment of malaria. Besides the potent antimalarial activity, numerous studies have unearthed the anticancer activity of artemisinin and hundreds of cytotoxic artemisinin derivatives have been reported in the past two decades. However, the direct protein target(s) and mode of actions of this mysterious structural and functional unique natural product are poorly studied. 

Prof. XIAO Youli’s group at CAS Center for Excellence in Molecular Plant Sciences, CAS Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, CAS, unveiled the protein targets and mechanism of action of artemisinin in cancer cell proteome.  

By utilizing an artemisinin scaffold derivated clickable chemical probe approach through chemical proteomics strategy, the research group could be able to "fish" and identified 79 protein targets of artemisinin in cancer cell proteome. Further study demonstrated that the true activator of artemisinin is heme Fe (II), which triggers the cleavage of the endoperoxide moiety, subsequently the carbon-centered radical is generated for targeting protein. In summary, three mechanism action models were proposed involved in artemisinin alkylation through protein binding capability of artemisinin or heme. Therefore, artemisinin might exert its unique anticancer activity through alkylation of multiple key proteins related to cell viability under an iron-rich environment within cancer cells.  

The findings and the developed strategy in this study will shed new light on the understanding of the mechanism of artemisinin bioactivity as well as anti-cancer effect.   

This study entitled “Profiling of Multiple Targets of Artemisinin Activated by Hemin in Cancer Cell Proteome” has been published online in ACS Chemical Biology on February 10, 2016.  

The work was funded by the “Thousand Talents Program” young investigator award, the National Nature Science Foundation of China, Chinese Academy of Sciences and Science and Technology Commission of Shanghai Municipality. 

Schematic illustration: Chemical proteomics profiling of heme-activated artemisinin binding proteins in cancer proteome (Image by Prof. XIAO Youli’s group)