PRECLINICAL STUDIES Zelnorm, an agonist of 5-Hydroxytryptamine 4-receptor, acts as a potential antitumor drug by targeting JAK/STAT3 signaling Lei Zhang 1,2 & Qiaoling Song 1,2 & Xinxin Zhang 2 & Li Li 1,2 & Ximing Xu 1,2 & Xiaohan Xu 1 & Xiaoyu Li 2 & Zhuoya Wang 3 & Yuxi Lin 3 & Xin Li 3 & Mengyuan Li 1,2 & Fan Su 1 & Xin Wang 1,2 & Peiju Qiu 1,2 & Huashi Guan 1,2 & Yu Tang 1,2 & Wenfang Xu 2 & Jinbo Yang 1,2 & Chenyang Zhao 1,2 Received: 8 March 2019 /Accepted: 6 May 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 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 phosphory- lation 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. Keywords Zelnorm . Drug repurposing . JAK/STAT3 . Antitumor . High-throughput screening Introduction The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway regulates signaling transduction and downstream gene expression, which are in- volved in processes such as cell proliferation, cell survival, immunity and tumor formation [1–4]. There are four JAKs (JAK1, JAK2, JAK3 and TYK2) and seven STATs (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6) in mammalian cells [1]. After stimulation with cytokines, such as IL-6, IFNα, and IFNγ, the JAKs phosphorylate each other at tyrosine residues and then recruit STATs to the phosphorylated receptors. STATs are then tyrosine- phosphorylated by JAKs and consequently translocated to the nucleus to induce target gene transcription [5–10]. Aberrant activation of the JAK/STAT signaling pathway causes many diseases, including autoimmune disease, graft- versus-host disease, hematologic malignancies, and solid tu- mors [11–16]. JAK2 mutations might lead to lymphoma and leukemia [17], and STAT3 and STAT5 mutations would in- duce JAK/STAT signaling pathway activation in NK and T cells, which can lead to leukemia [18]. Among the seven STATs, STAT3 was recognized as the most critical in tumor formation and progression [19, 20]. STAT3 hyperactivation has been identified in multiple types of cancers and is respon- sible for cancer growth and metastasis [21–23]. Therefore, the JAK/STAT signaling pathway, especially STAT3 signaling, is a promising drug target for cancer treatment. Compared with traditional de novo drug discovery, drug repurposing would take advantage of existing safety profiles, reduce development timelines and decrease the cost to market [24–26]. Drug repurposing refers to the identification of new clinical applications for existing drugs and compounds. Repurposed drug discovery would also take advantage of the published information on pharmacokinetics, side effects and interactions with other drugs, which will certainly Lei Zhang and Qiaoling Song contributed equally to this work. * Chenyang Zhao zhaocy@ouc.edu.cn 1 School of Medicine and Pharmacy, Ocean University of China, 23 East Hong Kong Road, Qingdao 266071, Shandong, China 2 Innovation Platform of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266100, Shandong, China 3 School of Life Science, Lanzhou University, Lanzhou 730000, Gansu, China Investigational New Drugs https://doi.org/10.1007/s10637-019-00790-8