Targeting 5-HT to Alleviate Dose-Limiting Neurotoxicity in Nab-Paclitaxel-Based Chemotherapy.
10.1007/s12264-025-01398-0
- Author:
Shuangyue PAN
1
;
Yu CAI
1
;
Ronghui LIU
1
;
Shuting JIANG
1
;
Hongyang ZHAO
1
;
Jiahong JIANG
2
;
Zhen LIN
2
;
Qian LIU
2
;
Hongrui LU
2
;
Shuhui LIANG
2
;
Weijiao FAN
2
;
Xiaochen CHEN
2
;
Yejing WU
2
;
Fangqian WANG
3
;
Zheling CHEN
4
;
Ronggui HU
5
;
Liu YANG
6
Author Information
1. Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310000, China.
2. Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China.
3. Department of Orthopedic Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China. wfqzju@zju.edu.cn.
4. Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China. chenzheling@hmc.edu.cn.
5. Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China. coryhu00@gmail.com.
6. Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China. yangliu@hmc.edu.cn.
- Publication Type:Journal Article
- Keywords:
Chemotherapy-induced peripheral neurotoxicity;
Nab-paclitaxel;
Serotonin;
Venlafaxine
- MeSH:
Paclitaxel/toxicity*;
Animals;
Albumins/adverse effects*;
Serotonin/metabolism*;
Mice;
Humans;
Male;
Female;
Venlafaxine Hydrochloride/therapeutic use*;
Neurotoxicity Syndromes/metabolism*;
Middle Aged;
Schwann Cells/metabolism*;
Peripheral Nervous System Diseases/drug therapy*;
Antineoplastic Agents
- From:
Neuroscience Bulletin
2025;41(7):1229-1245
- CountryChina
- Language:English
-
Abstract:
Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe dose-limiting adverse event of chemotherapy. Presently, the mechanism underlying the induction of CIPN remains unclear, and no effective treatment is available. In this study, through metabolomics analyses, we found that nab-paclitaxel therapy markedly increased serum serotonin [5-hydroxtryptamine (5-HT)] levels in both cancer patients and mice compared to the respective controls. Furthermore, nab-paclitaxel-treated enterochromaffin (EC) cells showed increased 5-HT synthesis, and serotonin-treated Schwann cells showed damage, as indicated by the activation of CREB3L3/MMP3/FAS signaling. Venlafaxine, an inhibitor of serotonin and norepinephrine reuptake, was found to protect against nerve injury by suppressing the activation of CREB3L3/MMP3/FAS signaling in Schwann cells. Remarkably, venlafaxine was found to significantly alleviate nab-paclitaxel-induced CIPN in patients without affecting the clinical efficacy of chemotherapy. In summary, our study reveals that EC cell-derived 5-HT plays a critical role in nab-paclitaxel-related neurotoxic lesions, and venlafaxine co-administration represents a novel approach to treating chronic cumulative neurotoxicity commonly reported in nab-paclitaxel-based chemotherapy.
