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

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

  • J Mol Med (Berl). 2022 Dec 7. doi: 10.1007/s00109-022-02273-5.
Jia Qiu # 1 2 Tianhong Yang # 1 Yali Long # 1 Peng He 1 3 Wanqing Shen 1 Bing Zhang 1 Xinchong Shi 1 Lei Peng 1 Zhoulei Li 1 Xiangsong Zhang 4
Affiliations

Affiliations

  • 1 Department of Nuclear Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
  • 2 Medical Imaging Center, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
  • 3 Department of Ultrasound Medicine & Ultrasonic Medical Engineering Key Laboratory of Nanchong City, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.
  • 4 Department of Nuclear Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. zhxiangs@mail.sysu.edu.cn.
  • # Contributed equally.
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.

Keywords

Ascorbic acid; Castration-resistant prostate cancer; Mitochondrial respiration inhibitor.

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