The Anticancer Mechanism Of Ibrutinib And Eupalinolide A Targeting Thioredoxin Reductase

Reactive oxygen species?ROS?is harmful metabolite for organism,and it is also the important signal in cellular metabolism.Cells sustain the balance of ROS to avoid suffer oxidative stress.Due to the properties of cancer such as unlimited growth and easy metastasis,we choose the ROS-promotion anticancer stratergy by targeting thioredoxin reductase to selectively kill cancer cells.Thioredoxin system is an important antioxidant system,which is composed of thioredoxin?Trx?,thioredoxin reductase?TrxR?and NADPH.Not only can Trx reduce peroxiredoxin to catalyze H₂O₂,it can also regulate several cellular pathways to modulate the cellular metabolism.Because Trx activity is determined by the activity of TrxR and TrxR is high expressed in most cancer cells,we can selectively raise the ROS level of cancer cells if we can selectively inhibit the TrxR activity.The thesis has reported the anticancer mechanism of Bruton's tyrosine kinase inhibitor ibrutinib?IBT?and the component of traditional medicine Eupatorium,Eupalinolide A?EA?,can selectively inhibit the activity of mammal TrxR,and then induce the ROS promotion,finally promote cancer cells ROS-induced apoptosis.The dock stimulation assay indicated that TrxR could be a potent target of IBT,and the cell assay determined that IBT can selectively inhibit intracellular TrxR activity.Further researches IBT can promote cancer cells ROS production and destroy the redox balance.Knockdown of TrxR1 and pharmacological inhibition of TrxR both demonstrated that TrxR activity was involved in the IBT-induced cytotoxicity.While NAC and BSO assay demonstrated that ROS-promotion was also involved in the IBT-induced cytotoxicity.Finally we determined that IBT kill cancer cells by apoptosis.Further studies determined EA was also involved in the anticancer mechanism of targeting TrxR.We preliminarily researched the anticancer mechanism of Ibrutinib and Eupalinolide A as TrxR inhibitors,and determined that TrxR was a potent target of IBT and EA.and provide theoretical basis and experimental foundation for EA's further study and IBT's clinical therapy.