Targeting thioredoxin reductase by micheliolide contributes to radiosensitizing and inducing apoptosis of HeLa cells

Abstract

Inhibition of thioredoxin reductase (TrxR) is a crucial strategy for the discovery of antineoplastic drugs and radiosensitizers. As an anticancer candidate derived from Michelia, micheliolide (MCL) is converted readily from parthenolide (PTL), and has better stability and solubility than PTL. However, the anticancer mechanism of MCL has not been fully dissected. We present here for the first time that MCL-targeted inhibition of TrxR not only promotes oxidative stress-mediated HeLa cell apoptosis but also sensitizes ionizing radiation (IR) treatment. Further mechanistic studies demonstrate that MCL covalently binds to Sec at position 498 of TrxR to restrain the biological function of TrxR. It exhibits the inhibition of TrxR activity, enhancement of oxidized Trx, and sensitization of IR in the cellular environment, accompanied by the accumulation of reactive oxygen species (ROS) and the collapse of the intracellular redox balance. In addition, HeLa-shTrxR1 cells with knockdown of TrxR were more sensitive than the HeLa-shNT cells to either MCL-treated or IR-induced cytotoxicity, ROS, and apoptosis, suggesting that inhibition of TrxR by MCL is likely responsible for increased cytotoxicity and enhanced radiation response. These findings further establish the mechanistic understanding and preclinical data to support the further investigation of MCL's potential as a prospective radiosensitizer and cancer chemotherapeutic agent.