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Zileuton inhibits arachidonate-5-lipoxygenase to exert antitumor effects in preclinical cervical cancer models

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Abstract

Background

Inhibitors of arachidonate lipoxygenase 5 (ALOX5) exhibit anticancer activity. Zileuton is an FDA-approved drug for treating asthma and an ALOX5 inhibitor. This study evaluated the efficacy of zileuton in cervical cancer, determined the molecular mechanism of action, and assessed ALOX5 expression in cervical cancer patients.

Methods

The effects of zileuton were evaluated using cervical cancer cell lines and xenograft mouse models. Loss-of-function analysis of ALOX5 was performed using siRNA. The levels of ALOX5 and 5-HETE were determined using immunohistochemistry and ELISA.

Results

Zileuton resulted in cell proliferation inhibition and apoptosis induction in a dose-dependent manner, regardless of cellular origin or HPV infection. In two independent cervical cancer xenograft mouse models, zileuton at nontoxic doses significantly prevented tumor formation and decreased tumor growth. Zileuton acts on cervical cancer cells by inhibiting the ALOX5-5-HETE axis. Of note, ALOX5-5-HETE was significantly upregulated in cervical cancer compared with normal tissue. Inhibition of ALOX5 via the siRNA approach mimics the inhibitory effects of zileuton and confirms the roles of ALOX5 in cervical cancer.

Conclusions

Our work demonstrates that the ALOX5-5-HETE axis is activated in cervical cancer, with important roles in growth and survival, and this can be therapeutically targeted by zileuton. Our findings also provide preclinical evidence to assess the efficacy of zileuton in cervical cancer in clinical settings.

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Data availability

Data will be made available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by a research grant provided by the National Natural Science Foundation of China (81974410).

Author information

Author notes

  1. Liling Li and Yifang Xiao are co-first authors and contributed equally to this work.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Hubei Provincial Hospital of Integrated Chinese and Western Medicine, Wuhan, China

    Liling Li, Yifang Xiao & Zhengzheng Xu

  2. Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Rd 1095, Qiaokou District, Wuhan, 430030, China

    Shaoshuai Wang

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  1. Liling Li
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  2. Yifang Xiao
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Contributions

SSW designed the experiments, supervised the project and analyzed the data; LLL and YFX performed the experiments, analyzed the data and wrote the manuscript; ZZX performed the experiments; All authors revised the manuscript.

Corresponding author

Correspondence to Shaoshuai Wang.

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All authors report no conflict of interest.

Ethical approval

This study was conducted in accordance with the ethical principles of the Declaration of Helsinki.

Research involving human participants and/or animals

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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This study was approved by the ethics committee of Tongji Hospital. Written informed consent was obtained from all patients under institutional review board-approved protocols.

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Li, L., Xiao, Y., Xu, Z. et al. Zileuton inhibits arachidonate-5-lipoxygenase to exert antitumor effects in preclinical cervical cancer models. Cancer Chemother Pharmacol 88, 953–960 (2021). https://doi.org/10.1007/s00280-021-04343-w

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  • DOI: https://doi.org/10.1007/s00280-021-04343-w

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