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

Lei Zhang; Qiaoling Song; Xinxin Zhang; Li Li; Ximing Xu; Xiaohan Xu; Xiaoyu Li; Zhuoya Wang; Yuxi Lin; Xin Li; Mengyuan Li; Fan Su; Xin Wang; Peiju Qiu; Huashi Guan; Yu Tang; Wenfang Xu; Jinbo Yang; Chenyang Zhao

doi:10.1007/s10637-019-00790-8

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

Invest New Drugs. 2020 Apr;38(2):311-320. doi: 10.1007/s10637-019-00790-8. Epub 2019 May 14.

Authors

Lei Zhang^{1

2}, Qiaoling Song^{1

2}, Xinxin Zhang², Li Li^{1

2}, Ximing Xu^{1

2}, Xiaohan Xu¹, Xiaoyu Li², Zhuoya Wang³, Yuxi Lin³, Xin Li³, Mengyuan Li^{1

2}, Fan Su¹, Xin Wang^{1

2}, Peiju Qiu^{1

2}, Huashi Guan^{1

2}, Yu Tang^{1

2}, Wenfang Xu², Jinbo Yang^{1

2}, Chenyang Zhao^{4

5}

Affiliations

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.
⁴ School of Medicine and Pharmacy, Ocean University of China, 23 East Hong Kong Road, Qingdao, 266071, Shandong, China. [email protected].
⁵ Innovation Platform of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266100, Shandong, China. [email protected].

PMID: 31087223
DOI: 10.1007/s10637-019-00790-8

Abstract

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.

Keywords: Antitumor; Drug repurposing; High-throughput screening; JAK/STAT3; Zelnorm.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use*
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
G1 Phase Cell Cycle Checkpoints / drug effects
Humans
Indoles / pharmacology
Indoles / therapeutic use*
Janus Kinases / antagonists & inhibitors*
Janus Kinases / metabolism
Mice, Nude
Neoplasms / drug therapy*
Neoplasms / genetics
Neoplasms / metabolism
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use*
Receptors, Serotonin, 5-HT4 / genetics
STAT3 Transcription Factor / antagonists & inhibitors*
STAT3 Transcription Factor / metabolism
Serotonin 5-HT4 Receptor Agonists / pharmacology
Serotonin 5-HT4 Receptor Agonists / therapeutic use*
Signal Transduction / drug effects

Substances

Antineoplastic Agents
Indoles
Protein Kinase Inhibitors
STAT3 Transcription Factor
STAT3 protein, human
Serotonin 5-HT4 Receptor Agonists
Receptors, Serotonin, 5-HT4
tegaserod
Janus Kinases