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Repurposing of the Antipsychotic Trifluoperazine Induces SLC7A11/GPX4- Mediated Ferroptosis of Oral Cancer via the
Sheng-Chieh Tsai1, Po-Chih Chang2,3,4, Yu Tong Lin1
1Division of Pharmacology and Traditional Chinese Medicine, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City 80708, Taiwan.
Abstract:
Ferroptosis, a mode of cell death characterized by iron-dependent phospholipid peroxidation, has a substantial therapeutic potential for the treatment of various cancers. This study investigated the effects of trifluoperazine (TFP), an FDA-approved drug traditionally utilized for mental health disorder, on oral cancer cells, with a particular focus on the mechanisms involved in its potential anti-tumor properties. Our findings indicate that TFP significantly elevates the levels of lipid-derived reactive oxygen species (ROS) and induces ferroptotic cell death in oral cancer cells through pathways involving autophagy, the SLC7A11/GPX4 axis, and mitochondrial damage. Additionally, molecular docking analyses revealed that TFP acts as an inhibitor of GPX4. The elevated expression level of GPX4 in oral cancer biopsies was also found to correlate with a poor prognosis. Together, these results provide evidence that TFP selectively induces GPX4-mediated, autophagy-dependent ferroptosis, thereby exerting anti-cancer effects against oral cancer and preventable death.
Insights
Trifluoperazine (TFP) induces ferroptosis, a cell death pathway, in oral cancer cells. This FDA-approved drug shows potential for treating oral cancer by targeting the GPX4 axis and promoting cell death.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Ferroptosis, an iron-dependent cell death, presents therapeutic potential for cancer treatment.
- Trifluoperazine (TFP), an antipsychotic medication, has unexplored anti-cancer properties.
- Oral cancer remains a significant global health challenge requiring novel therapeutic strategies.
Purpose of the Study:
- To investigate the anti-cancer effects of trifluoperazine (TFP) on oral cancer cells.
- To elucidate the mechanisms underlying TFP-induced cell death, focusing on ferroptosis.
- To explore the role of the SLC7A11/GPX4 axis and autophagy in TFP's anti-tumor activity.
Main Methods:
- Treatment of oral cancer cells with trifluoperazine (TFP).
- Measurement of lipid-derived reactive oxygen species (ROS) levels.
- Analysis of ferroptosis markers, autophagy, SLC7A11/GPX4 axis, and mitochondrial integrity.
- Molecular docking simulations to assess TFP's interaction with GPX4.
- Examination of GPX4 expression in oral cancer patient biopsies.
Main Results:
- Trifluoperazine (TFP) significantly increased lipid ROS and induced ferroptotic cell death in oral cancer cells.
- TFP's effects were mediated through pathways involving autophagy, the SLC7A11/GPX4 axis, and mitochondrial damage.
- Molecular docking confirmed TFP as a GPX4 inhibitor, and elevated GPX4 expression correlated with poor prognosis in oral cancer patients.
Conclusions:
- Trifluoperazine (TFP) selectively induces GPX4-mediated, autophagy-dependent ferroptosis in oral cancer.
- TFP demonstrates significant anti-cancer effects against oral cancer, offering a potential therapeutic strategy.
- Targeting ferroptosis via TFP could be a promising approach to prevent oral cancer mortality.
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