Targeting 5-HT to Alleviate Dose-Limiting Neurotoxicity in Nab-Paclitaxel-Based Chemotherapy
Shuangyue Pan1,2 · Yu Cai1,2 · Ronghui Liu1,2 · Shuting Jiang1,2 · Hongyang Zhao1,2 · Jiahong Jiang2 · Zhen Lin2 · Qian Liu2 · Hongrui Lu2 · Shuhui Liang2 · Weijiao Fan2 · Xiaochen Chen2 · Yejing Wu2 · Fangqian Wang6 · Zheling Chen2 · Ronggui Hu4,5,7 · Liu Yang2,31 Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310000, China
2 Cancer Center, Department of Medical Oncology, Zhejiang Provincial People’s Hospital, Afliated People’s Hospital, Hangzhou Medical College, Hangzhou 310014, China
3 Zhejiang Provincial Clinical Research Center for Head and Neck Cancer, Zhejiang Key Laboratory of Precision Medicine Research on Head and Neck Cancer, Zhejiang Province Key Disciplines in Traditional Chinese Medicine-Integrated Traditional Chinese and Western Medicine Clinical Oncology, Hangzhou 310014, China
4 Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Afliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
5 Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou 310000, China
6 Department of Orthopedic Surgery, Second Afliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
7 Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-machine Integration, State Key Laboratory of Brain-machine Intelligence, Zhejiang University, Hangzhou 311121, China
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.
Keywords
Chemotherapy-induced peripheral neurotoxicity; Nab-paclitaxel; Serotonin; Venlafaxine
