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Repurposed pizotifen malate targeting NRF2 exhibits anti-tumor activity through inducing ferroptosis in esophageal squamous cell carcinoma

Oncogene volume 42, pages 1209–1223 (2023)Cite this article

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Abstract

Targeted therapy attempts are needed to enhance esophageal squamous cell carcinoma (ESCC) patients’ overall survival and satisfaction of life. Nuclear factor erythroid 2-related factor 2 (NRF2), as a high-confidence cancer driver gene, controls the antioxidant response, metabolic balance and redox homeostasis in cancer and is regarded as a potent molecular target for cancer treatment. Here, we attempted to find a new NRF2 inhibitor and study the underlying molecular mechanism in ESCC. We found that up-regulated NRF2 protein was negatively correlated with patient prognosis and promoted tumor proliferation in ESCC. Moreover, Pizotifen malate (PZM), a FDA-approved medication, bound to the Neh1 domain of NRF2 and prevented NRF2 protein binding to the ARE motif of target genes, suppressing transcription activity of NRF2. PZM treatment suppressed tumor development in ESCC PDX model by inducing ferroptosis via down-regulating the transcription of GPX4, GCLC, ME1 and G6PD. Our study illustrates that the over expression of NRF2 indicates poor prognosis and promotes tumor proliferation in ESCC. PZM, as a novel NRF2 inhibitor, inhibits the tumor growth by inducing ferroptosis and elucidates a potent NRF2-based therapy strategy for patients with ESCC.

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Fig. 1: NRF2 is highly expressed in ESCC and is negatively correlated with patient survival probability.
Fig. 2: PZM directly binds with NRF2 and inhibits its transcriptional activity.
Fig. 3: PZM suppresses the proliferation of ESCC by targeting NRF2.
Fig. 4: PZM induces ferroptosis in ESCC by proteomics evolution.
Fig. 5: PZM induces ferroptosis through increasing ROS and lipid peroxidation in ESCC.
Fig. 6: PZM inhibits ESCC patient-derived xenograft (PDX) tumor growth in vivo.
Fig. 7: PZM inhibits the growth of residual model after resection of ESCC.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We’d like to express our gratitude to Dr. Fred Bogott for the language revision. This work was supported by the National Natural Science Foundations of China (No. 81872335), National Natural Science Youth Foundation (No. 81902486), the Natural Science Foundation of Henan (No. 161100510300), the Central Plains Science and Technology Innovation Leading Talents (No. 224200510015), the Science and Technology Project of Henan Province (No. 212102310187), National Natural Science Foundation of China (32100532), China Postdoctoral Science Foundation (2021M692936), the Supporting Plan of Zhengzhou University Youth Innovation Team (32320442).

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  1. These authors contributed equally: Xinyu He, Yubing Zhou.

Authors and Affiliations

  1. The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China

    Xinyu He, Yubing Zhou, Wenjing Chen, Xiaokun Zhao, Lina Duan, Hao Zhou, Mingzhu Li, Yin Yu, Jimin Zhao, Yaping Guo, Yanan Jiang, Zigang Dong & Kangdong Liu

  2. China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, Henan, China

    Xinyu He, Yubing Zhou, Wenjing Chen, Xiaokun Zhao, Lina Duan, Mingzhu Li, Yin Yu, Yanan Jiang, Zigang Dong & Kangdong Liu

  3. State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, 450000, Henan, China

    Jimin Zhao, Yanan Jiang, Zigang Dong & Kangdong Liu

  4. Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, 450000, Henan, China

    Jimin Zhao, Yanan Jiang & Kangdong Liu

  5. Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, 450000, Henan, China

    Jimin Zhao, Zigang Dong & Kangdong Liu

  6. Basic Medicine Sciences Research Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450000, Henan, China

    Huihui Gu & Kangdong Liu

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Contributions

Conceptualization: KL, ZD and YJ. Data curation: XH. Formal analysis: YZ. Funding acquisition: KL, YG, and YJ. Investigation: XH, YZ, YY, ML, WC, XZ, and LD. Methodology: XH and YZ. Project administration: ZD, KL, and YJ. Resources: ZD, KL, and YJ. Software: XH and YG. Supervision: KL and YJ. Validation: XH and YZ. Visualization: XH, JZ, HZ, and HG. Roles/Writing-original draft: XH and YJ. Writing-review and editing: KL and YJ.

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Correspondence to Yanan Jiang, Zigang Dong or Kangdong Liu.

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He, X., Zhou, Y., Chen, W. et al. Repurposed pizotifen malate targeting NRF2 exhibits anti-tumor activity through inducing ferroptosis in esophageal squamous cell carcinoma. Oncogene 42, 1209–1223 (2023). https://doi.org/10.1038/s41388-023-02636-3

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