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Xanthatin Promotes Apoptosis via Inhibiting Thioredoxin Reductase and Eliciting Oxidative Stress
Ruijuan Liu1,2, Danfeng Shi3, Junmin Zhang2
1State Key Laboratory of Applied Organic Chemistry , Lanzhou University , Lanzhou 730000 , China.
Abstract:
Xanthatin (XT), a naturally occurring sesquiterpene lactone presented in cocklebur ( Xanthium strumarium L.), is under development as a potential anticancer agent. Despite the promising anticancer effect of XT, the molecular mechanism underlying its cellular action has not been well elucidated. The mammalian thioredoxin reductase (TrxR) enzymes, the essential seleno-flavoproteins containing a penultimate selenocysteine (Sec) residue at the C-terminus, represent a promising target for cancer chemotherapeutic agents. In this study, XT inhibits both the purified TrxR and the enzyme in cells. The possible binding mode of XT with the TrxR protein is predicted by the covalent docking method. Mechanism studies reveal that XT targets the Sec residue of TrxR and inhibits the enzyme activity irreversibly. Simultaneously, the inhibition of TrxR by XT promotes the oxidative stress-mediated apoptosis of HeLa cells. Importantly, the knockdown of the enzyme sensitizes the cells to XT treatment. Targeting TrxR thus discloses a novel molecular mechanism in accounting for the cellular action of XT and provides insights into the development of XT as an anticancer agent.
Insights
Xanthatin, an anticancer compound, works by irreversibly inhibiting thioredoxin reductase (TrxR) in cancer cells. This mechanism promotes oxidative stress and cancer cell death, offering a new therapeutic strategy.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Xanthatin (XT) is a natural sesquiterpene lactone from Xanthium strumarium with potential anticancer properties.
- The precise molecular mechanisms of XT's anticancer effects require further elucidation.
- Mammalian thioredoxin reductase (TrxR) is a key seleno-flavoprotein and a potential target for cancer therapeutics.
Purpose of the Study:
- To investigate the molecular mechanism of Xanthatin's anticancer activity.
- To determine if Xanthatin targets thioredoxin reductase (TrxR).
- To explore the role of TrxR inhibition in XT-induced cancer cell apoptosis.
Main Methods:
- Inhibition assays using purified TrxR and TrxR within cells.
- Covalent docking simulations to predict XT binding mode to TrxR.
- Cellular studies involving TrxR knockdown and assessment of apoptosis.
- Oxidative stress measurements.
Main Results:
- Xanthatin irreversibly inhibits both purified TrxR and cellular TrxR activity.
- XT targets the selenocysteine (Sec) residue of TrxR.
- Inhibition of TrxR by XT induces oxidative stress and apoptosis in HeLa cancer cells.
- Knockdown of TrxR sensitizes cells to Xanthatin treatment.
Conclusions:
- Xanthatin's anticancer effect is mediated by the irreversible inhibition of thioredoxin reductase (TrxR).
- Targeting TrxR represents a novel molecular mechanism for XT's cellular action.
- These findings provide insights for developing Xanthatin as a targeted anticancer agent.
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