Prebiotic stachyose inhibits PRDX5 activity and castration-resistant prostate cancer development PMID: 39168191

ADC Targets in Oncology

2026-04-10

Prebiotic stachyose inhibits PRDX5 activity and castration-resistant prostate cancer development

Int J Biol Macromol. 2024 Oct;278(Pt 3):134844. doi: 10.1016/j.ijbiomac.2024.134844.

Rong Wang ¹ , Yu Pan ² , Lan Zhang ² , Jun Wang ³ , Jiang Ni ⁴ , Yang Ding ⁵ , Shaopeng Wang ⁶ , Jian Yin ⁷ , Lingwen Ding ⁸ , Xuebin Ran ⁹ , Shuangyi Fan ¹⁰ , Qiaoyang Sun ¹¹ , Soo Yong Tan ¹⁰ , H Phillip Koeffler ¹² , Jie Li ¹³ , Yuanyuan Mi ¹⁴ , Yong Q Chen ¹⁵

Affiliations

1. MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, China; School of Food Science and Technology, Jiangnan University, Wuxi, China.
2. MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, China.
3. First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China; Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, China.
4. Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, China.
5. College of Pharmacy, Pharmaceutical Series, China Pharmaceutical University, Nanjing, China.
6. Jiangnan University Medical Center, Jiangnan University, Wuxi, China.
7. Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology & School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, China.
8. Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
9. Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
10. Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
11. Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore, Singapore.
12. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, CA, Los Angeles, USA.
13. First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China. Electronic address: [email protected].
14. Affiliated Hospital of Jiangnan University, Jiangnan University, Wuxi, China. Electronic address: [email protected].
15. MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, Wuxi School of Medicine, Jiangnan University, Wuxi, China; School of Food Science and Technology, Jiangnan University, Wuxi, China. Electronic address: [email protected].

Abstract

Stachyose (STA) is a prebiotic with poor oral bioavailability. In this study, we developed stachyose caproate (C6-STA), as a novel STA derivative, to demonstrate its high adsorption rate via oral administration. Pharmacokinetic analysis reveals that after absorption, the STA derived from C6-STA reaches its highest peak in the blood, liver, and kidney at 20 min, 30 min, and 12-24 h, with approximate levels of 1200 μg/mL, 0.14 μg/mL, and 0.2-0.3 μg/mL, respectively. In addition, the accumulation of STA in prostate tissues of mice with castration-resistant prostate Cancer (CRPC) (1.75 μg/mg) is 10-fold higher than that in normal prostate tissues (0.14 μg/mg). The analysis also reveals that C6-STA has t_1/2 of 12.8 h and T_max of 0.25 h, indicating that it has the potential to be used as a promising drug in clinical practice. The toxicological evaluation shows no obvious side effects of C6-STA in mice administered with a 0.2 g/kg intragastric dose. Pharmacodynamic analysis and mechanism investigation of C6-STA show its ability to inhibit peroxiredoxin 5 (PRDX5) enzyme activity, disrupt PRDX5-nuclear factor erythroid 2-related factor 2 (NRF2) interaction, and decrease NAD(P)H quinone dehydrogenase 1 (NQO1) levels. NQO1 decrease further causes the accumulation of quinone radicals, which ultimately leads to the Apoptosis of LNCaP cell-derived drug-tolerant persister (DTP) cells and slows CRPC progression. Our study discovered the anti-tumor activity of stachyose and shows that prebiotics have biological functions in vivo besides in the gut. Further investigation of C6-STA, especially in CRPC patients, is warranted.

Keywords

Castration-resistant prostate cancer; Drug-tolerant persister; Nuclear factor erythroid 2-related factor 2; Peroxiredoxin 5; Stachyose; Stachyose caproate.