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Published on: March 15, 2024
Dihydroartemisinin Triggers Ferroptosis in Multidrug-Resistant Leukemia Cells
Xueyan Zhang1,2, Ziying Ai2, Zhewen Zhang2
1Institute of Biochemistry and Molecular Biology and School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China.
Abstract:
The molecular mechanisms and role of ferroptosis in tumor drug resistance remain unclear. In this study, we found that multidrug-resistant (MDR) K562/adriamycin (ADM) leukemia cells possessed higher glutathione (GSH) levels and iron-regulatory protein 2 (IRP2), transferrin receptor, ferritin heavy chain 1 (FTH1), and peroxidase-4 (GPX4) expression than parental drug-sensitive K562 leukemia cells. These elevations might have increased the antioxidant ability of K562/ADM cells and granted them increased buffering capacity against iron disorder, protecting them from ferroptosis and favoring drug resistance. However, dihydroartemisinin (DHA) restrained MDR K562/ADM cell viability and enhanced the sensitivity to ADM by strengthening ferroptosis induced by downregulation of GSH levels and GPX4, IRP2, and FTH expression, upregulation of reactive oxygen species (ROS) levels, and the consequent suppression of total serine/threonine kinase (AKT), total mammalian target of rapamycin (t-mTOR), phosphorylated mTOR (p-mTOR), and p-mTOR/t-mTOR levels. Moreover, compared with K562 cells, MDR K562/ADM cells exhibited greater ROS increases, GSH decreases, and viability rescue after ferroptosis inhibitor treatment owing to further suppression of FTH1, GPX4, p-mTOR, and p-mTOR/t-mTOR. Collectively, the increase in oxidative damage and the blockade of antioxidant defence shaped DHA-induced ferroptosis, which was responsible for the sensitivity of MDR leukemia cells to DHA. Regulating iron homeostasis/ROS/AKT/mTOR might be a potential chemotherapeutic strategy for sensitizing drug-resistant leukemia.
Insights
Multidrug-resistant leukemia cells resist ferroptosis via elevated glutathione and iron proteins. Dihydroartemisinin combats this by inducing ferroptosis, offering a potential strategy for drug-resistant leukemia treatment.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Ferroptosis, a form of regulated cell death, plays an unclear role in tumor drug resistance.
- Multidrug-resistant (MDR) leukemia cells exhibit altered iron metabolism and antioxidant defenses.
Purpose of the Study:
- To investigate the role of ferroptosis in multidrug-resistant leukemia.
- To explore dihydroartemisinin (DHA) as a potential therapeutic agent to overcome drug resistance by inducing ferroptosis.
Main Methods:
- Comparison of ferroptosis-related markers (glutathione, IRP2, FTH1, GPX4) between drug-sensitive and resistant leukemia cells.
- Treatment of resistant cells with DHA and assessment of cell viability, ferroptosis markers, reactive oxygen species (ROS), and signaling pathways (AKT/mTOR).
- Evaluation of ferroptosis inhibitor effects on resistant cells.
Main Results:
- MDR leukemia cells showed higher glutathione levels and expression of iron-related proteins (IRP2, FTH1, GPX4), conferring resistance to ferroptosis.
- DHA treatment reduced MDR cell viability by inducing ferroptosis through decreased glutathione, altered protein expression, increased ROS, and suppressed AKT/mTOR signaling.
- Ferroptosis inhibitors partially rescued MDR cells, indicating ferroptosis's role in DHA sensitivity.
Conclusions:
- Elevated antioxidant capacity and iron homeostasis contribute to ferroptosis resistance in MDR leukemia.
- DHA sensitizes MDR leukemia cells by inducing ferroptosis via oxidative damage and suppression of antioxidant defenses.
- Targeting iron homeostasis, ROS, and the AKT/mTOR pathway presents a promising strategy for overcoming leukemia drug resistance.
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