Cynaropicrin Targeting Thioredoxin Reductase As A Promising Anticancer Agent

Cancer is considered as one of the highly mortal diseases globally.This is largely due to the lack of efficacious medicines for tumors,and thus development of potent anticancer agents is urgently needed.The stability of internal redox environment is critical for the surviving ability of cells,but cancer cells exhibit higher levels of ROS production and chronic signs of oxidative stress compared to normal cells.Therefore,this specialty has been considered as a promising vulnerability against cancer.Inhibition of antioxidant system in already-sensitized cancer cells to generate the superfluous ROS is regarded as a novel anticancer way.But broad inhibition also kills normal cells,which is highly unwanted in a clinical setting.Hence,strategies aimed to cause selective oxidative stress in tumor while sparing normal tissue,might be specifically effective for oncotherapy.The thioredoxin(Trx)system is crucial to the survival ability of cells and its expression is up-regulated in many human tumors.Recently,increasing evidence has been established that mammalian thioredoxin reductase(TrxR),a selenocysteinecontaining protein and the core component of the thioredoxin system,is a promising therapeutic target.The sesquiterpene lactone compound cynaropicrin(CYN),a major component of Cynara scolymus L.,has shown multiple pharmacological functions,especially the anticancer effect,in many experimental models.Most of these functions are concomitant with the production of reactive oxygen species(ROS).Nevertheless,the target of this promising natural anticancer product in redox control has rarely been explored.Based on the above,the anticancer activity and mechanism of CYN were studied in this paper.The main contents include:1.Firstly,we briefly introduced the production and regulation of ROS in cells,and the relationship between cancer cells and ROS was summarized.In addition,a simple summary of the current anticancer strategies based on ROS were presented,and the thioredoxin system and its significance in tumor therapy were introduced.Finally,we introduced the cynaropicrin(CYN),including its source,structural characteristics,biological and physiological activity.2.Second,we showed that CYN induces apoptosis of Hela cells.Mechanistic studies demonstrated that CYN impinges on the thioredoxin system via inhibition of TrxR,which leads to Trx oxidation and ROS accumulation in HeLa cells.Particularly,the cytotoxicity of CYN is enhanced through the genetic knockdown of TrxR,supporting the pharmacological effect of CYN is relevant to its inhibition of TrxR.Together,our studies reveal an unprecedented mechanism accounting for the anticancer effect of CYN and identify a promising therapeutic agent worthy of further development for cancer therapy.