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J Cancer 2024; 15(13):4430-4447. doi:10.7150/jca.96448 This issue Cite

Research Paper

Reversal of Platinum-based Chemotherapy Resistance in Ovarian Cancer by Naringin Through Modulation of The Gut Microbiota in a Humanized Nude Mouse Model

Bingqing Xie^1†, Xiaoni Zhou^1†, Chuanlin Luo², Yilin Fang², Yufei Wang⁴, Jing Wei², Liping Cai^1✉, Tingtao Chen^1,2,3✉

1. Department of Obstetrics & Gynecology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi, China.
2. National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, Jiangxi, China.
3. School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang,330031, Jiangxi, China.
4. Queen Mary School, Nanchang University, Nanchang 330031, China.
† Both authors have contributed equally to this work and share the first authorship.

✉ Corresponding authors: Dr. Tingtao Chen, chentingtao1984com; National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, School of Pharmacy, Jiangxi Medical College, Nanchang University, No. 1299 Xuefu Avenue, Honggutan District, Nanchang 330031, Jiangxi Province, China. Dr. Liping Cai, cailiping2550com, Department of Obstetrics & Gynecology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, No. 17, Yongwai Zhengjie, Donghu District, Nanchang 330006, Jiangxi Province, China. More

Abstract

As a chemotherapy agent, cisplatin (DDP) is often associated with drug resistance and gastrointestinal toxicity, factors that severely limit therapeutic efficacy in patients with ovarian cancer (OC). Naringin has been shown to increase sensitivity to cisplatin, but whether the intestinal microbiota is associated with this effect has not been reported so far. In this study, we applied a humanized mouse model for the first time to evaluate the reversal of cisplatin resistance by naringin, as well as naringin combined with the microbiota in ovarian cancer. The results showed that naringin combined with Bifidobacterium animalis subsp. lactis NCU-01 had an inhibitory effect on the tumor, significantly reducing tumor size (p<0.05), as well as the concentrations of serum tumor markers CA125 and HE4, increased the relative abundance of Bifidobacterium and Bacteroides, inhibit Toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB)-induced intestinal inflammation and increase the expression of intestinal permeability-associated proteins ZO-1 (p<0.001) and occludin (p<0.01). In conclusion, the above data demonstrate how naringin combined with Bifidobacterium animalis subsp. lactis NCU-01 reverses cisplatin resistance in ovarian cancer by modulating the intestinal microbiota, inhibiting the TLR4/NF-κB signaling pathway and modulating the p38MAPK signaling pathway.

Keywords: ovarian cancer, cisplatin resistance, humanized model, inflammation, gut microbiota

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