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Trifluoperazine induces ferroptosis in acute myeloid leukemia by suppressing the Nrf2/SLC7A11/GPX4 axis
Jing Xu1, Wanfang Yang2, Yaofang Zhang3
1School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, 030001, China; The Key Laboratory of Molecular Diagnosis and Treatment of Hematological Diseases of Shanxi Province, Taiyuan, 030001, China; Institute of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, 030001, China.
Abstract:
Acute myeloid leukemia (AML) remains a therapeutic challenge due to high relapse rates and limited treatment options. Drug repurposing offers a promising strategy to accelerate clinical translation. In this study, we investigated the anti-AML potential of the FDA-approved antipsychotic drug trifluoperazine (TFP) and explored its underlying mechanisms. We found that TFP markedly inhibits AML cell proliferation by inducing cell cycle arrest and apoptosis, while exhibiting minimal toxicity to normal human umbilical vein endothelial cells and bone marrow stromal cells. Mechanistically, TFP triggers impairments in mitochondrial activity and promotes the accumulation of reactive oxygen species (ROS), and induces ferroptosis, a form of iron-dependent cell death characterized by iron overload, glutathione depletion, and lipid peroxidation. The ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively rescued TFP-induced cell death. Moreover, TFP synergized with the ferroptosis inducer erastin to enhance ferroptotic cell death. At the molecular level, TFP suppressed the Nrf2/SLC7A11/GPX4 antioxidant axis, an effect that was reversible by the Nrf2 activator ML334. In an AML xenograft model, TFP monotherapy significantly inhibited tumor growth and alleviated hepatosplenomegaly. Importantly, TFP synergized with venetoclax, a standard AML therapy, to enhance antileukemic efficacy both in vitro and in vivo. Collectively, our findings identify TFP as a potent ferroptosis inducer in AML and suggest its potential as a repurposed therapeutic agent, either as monotherapy or in combination with venetoclax.
Insights
Trifluoperazine (TFP), an antipsychotic, effectively targets acute myeloid leukemia (AML) by inducing ferroptosis, a form of cell death. This repurposed drug shows promise as a monotherapy or in combination with venetoclax for AML treatment.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Acute myeloid leukemia (AML) presents significant therapeutic challenges with high relapse rates.
- Drug repurposing is a viable strategy to discover novel anti-AML agents.
- Limited treatment options necessitate the exploration of new therapeutic avenues.
Purpose of the Study:
- To investigate the anti-AML potential of trifluoperazine (TFP), an FDA-approved antipsychotic.
- To elucidate the mechanisms underlying TFP's anti-leukemic effects.
- To evaluate TFP's efficacy as a monotherapy and in combination with standard AML treatments.
Main Methods:
- Assessed TFP's impact on AML cell proliferation, cell cycle, and apoptosis.
- Investigated TFP's effects on mitochondrial activity, reactive oxygen species (ROS), and ferroptosis.
- Utilized ferroptosis inhibitors (Fer-1) and inducers (erastin) to confirm ferroptosis involvement.
- Examined TFP's molecular targets, including the Nrf2/SLC7A11/GPX4 axis.
- Evaluated TFP efficacy in an AML xenograft mouse model and in combination with venetoclax.
Main Results:
- TFP significantly inhibited AML cell proliferation, induced cell cycle arrest, and apoptosis with minimal toxicity to normal cells.
- TFP triggered ferroptosis by impairing mitochondrial function, increasing ROS, and suppressing the Nrf2/SLC7A11/GPX4 antioxidant pathway.
- Ferrostatin-1 reversed TFP-induced cell death, while erastin enhanced it, confirming ferroptosis induction.
- TFP monotherapy reduced tumor growth and hepatosplenomegaly in vivo.
- TFP demonstrated synergistic anti-leukemic effects when combined with venetoclax both in vitro and in vivo.
Conclusions:
- Trifluoperazine is a potent inducer of ferroptosis in acute myeloid leukemia cells.
- TFP exhibits significant anti-leukemic activity and synergizes with venetoclax.
- Repurposed TFP represents a promising therapeutic strategy for AML, potentially as monotherapy or combination treatment.
