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Zelnorm, an agonist of 5-Hydroxytryptamine 4-receptor, acts as a potential antitumor drug by targeting JAK/STAT3 signaling

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Summary

The Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays central roles in cancer cell growth and survival. Drug repurposing strategies have provided a valuable approach for developing antitumor drugs. Zelnorm (tegaserod maleate) was originally designed as an agonist of 5-hydroxytryptamine 4 receptor (5-HT4R) and approved by the FDA for treating irritable bowel syndrome with constipation (IBS-C). Through the use of a high-throughput drug screening system, Zelnorm was identified as a JAK/STAT3 signaling inhibitor. Moreover, the inhibition of STAT3 phosphorylation by Zelnorm was independent of its original target 5-HT4R. Zelnorm could cause G1 cell cycle arrest, induce cell apoptosis and inhibit the growth of a variety of cancer cells. The present study identifies Zelnorm as a novel JAK/STAT3 signaling inhibitor and reveals a new clinical application of Zelnorm upon market reintroduction.

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Funding

This work was supported by grants from the National Science and Technology Major Project for Significant New Drugs Development 2018ZX09735–004 and the “AoShan Talents” Program Supported by Qingdao National Laboratory for Marine Science and Technology 2017ASTCP-OS11 to J.B. Yang, the Startup Funding for Scientific Research of Ocean University of China to C.Y. Zhao and the Key Research and Development Plan of Shandong Province (No. GG201709250124) to X.Y. Li.

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  1. Lei Zhang and Qiaoling Song contributed equally to this work.

Authors and Affiliations

  1. School of Medicine and Pharmacy, Ocean University of China, 23 East Hong Kong Road, Qingdao, 266071, Shandong, China

    Lei Zhang, Qiaoling Song, Li Li, Ximing Xu, Xiaohan Xu, Mengyuan Li, Fan Su, Xin Wang, Peiju Qiu, Huashi Guan, Yu Tang, Jinbo Yang & Chenyang Zhao

  2. Innovation Platform of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266100, Shandong, China

    Lei Zhang, Qiaoling Song, Xinxin Zhang, Li Li, Ximing Xu, Xiaoyu Li, Mengyuan Li, Xin Wang, Peiju Qiu, Huashi Guan, Yu Tang, Wenfang Xu, Jinbo Yang & Chenyang Zhao

  3. School of Life Science, Lanzhou University, Lanzhou, 730000, Gansu, China

    Zhuoya Wang, Yuxi Lin & Xin Li

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  1. Lei Zhang
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Zhang, L., Song, Q., Zhang, X. et al. Zelnorm, an agonist of 5-Hydroxytryptamine 4-receptor, acts as a potential antitumor drug by targeting JAK/STAT3 signaling. Invest New Drugs 38, 311–320 (2020). https://doi.org/10.1007/s10637-019-00790-8

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