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Mitochondrial respiration inhibitor enhances the anti-tumor effect of high-dose ascorbic acid in castration-resistant prostate cancer

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Abstract

Previous evidences have demonstrated that anti-tumor effect of high-dose ascorbic acid is associated with the generation of reactive oxygen species (ROS) via autoxidation. Hypoxia induces therapy resistance in castration-resistant prostate cancer. As a mitochondrial respiration inhibitor, metformin has the potential to improve tumor oxygenation. In this study, we evaluate the anti-tumor effect of ascorbic acid combined with metformin in prostate cancer. We demonstrated that ascorbic acid inhibits prostate cancer cells proliferation by generating ROS, and metformin enhances the anti-tumor effects of ascorbic acid. Mechanistically, metformin reduces oxygen consumption rate and NADP+/NADPH value in prostate cancer cells, thereby increases the ROS content induced by ascorbic acid. In addition, our data demonstrated that ascorbic acid inhibits p-AKT signaling in a ROS-dependent pathway, leading to inhibition of p-mTOR expression. And metformin inhibits the p-mTOR expression by activating the AMPK signaling pathway, exerting a synergistic effect on tumor suppression with ascorbic acid. Furthermore, metformin improves tumor oxygenation, and the combined treatment effect of ascorbic acid and metformin were demonstrated in a xenograft model of prostate cancer. Taken together, our data demonstrate that metformin enhances the anti-tumor proliferation effect of ascorbic acid by increasing ROS content in castration-resistant prostate cancer. This provides a new strategy for the clinical application of high-dose ascorbic acid as an anti-tumor drug.

Key messages

  • Ascorbic acid inhibits tumor growth by inducing ROS generation.

  • As a mitochondrial respiration inhibitor, metformin inhibits cellular oxygen consumption rate to improve oxygenation of prostate cancer.

  • Metformin enhances anti-tumor effect of ascorbic acid by increasing ROS content.

  • Ascorbic acid inhibits the mTOR expression via PI3K-AKT pathway, and metformin inhibits the mTOR expression by inhibiting AMPK signaling in prostate cancer cells.

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Funding

This study was supported by the National Science Foundation of China (grant number 81901793), Project of National Major Scientific Instrument and Equipment Development (2013YQ03092306), and Project of Nanchong Science and Technology Bureau ( 19SXHZ0263).

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  1. Jia Qiu, Tianhong Yang, and Yali Long contributed equally to this work.

Authors and Affiliations

  1. Department of Nuclear Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

    Jia Qiu, Tianhong Yang, Yali Long, Peng He, Wanqing Shen, Bing Zhang, Xinchong Shi, Lei Peng, Zhoulei Li & Xiangsong Zhang

  2. Medical Imaging Center, The Second Affiliated Hospital of Nanchang University, Nanchang, China

    Jia Qiu

  3. Department of Ultrasound Medicine & Ultrasonic Medical Engineering Key Laboratory of Nanchong City, Affiliated Hospital of North Sichuan Medical College, Nanchong, China

    Peng He

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  1. Jia Qiu
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Contributions

XSZ and JQ had the original idea for this study. JQ, THY, and YLL designed the study, performed the experiments, and wrote the first draft of the manuscript. PH, WQS, and LP were responsible for analyzing the data and writing the manuscript. BZ, XCS, and ZLL were responsible for the project administration. All authors read an approved the final manuscript.

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Correspondence to Xiangsong Zhang.

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All experiments were approved by the Institutional Animal Care and Use Committee of the First Affiliated Hospital of Sun Yat-Sen University and conformed to the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals.

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Qiu, J., Yang, T., Long, Y. et al. Mitochondrial respiration inhibitor enhances the anti-tumor effect of high-dose ascorbic acid in castration-resistant prostate cancer. J Mol Med 101, 125–138 (2023). https://doi.org/10.1007/s00109-022-02273-5

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