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Discovery of YH677 as a cancer stemness inhibitor that suppresses triple-negative breast cancer growth and metastasis by regulating the TGF? signaling pathway

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WOS体系：
Pubmed体系：

收录情况： ◇ SCIE

作者：
Zhang Yuzhu[1,4] * ; Chen Jing[2,5] * ; Mi Dazhao[3] * ; Ling Jun[2,5] ; Li Huachao[4] ; He Peng[3] ; Liu Ning[3] ; Chen Qianjun[4] ; Chen Yihua[3] ; Huang Luqi[1] ;
机构： [1]National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China [2]School of Basic Medical Sciences, Ningxia Medical University, Ningxia, 750004, China [3]Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China [4]Breast Department, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510120, China [5]Key Laboratory of Fertility Maintenance Ministry of Education, Ningxia Medical University, Ningxia, 750004, China
出处：
DOI： 10.1016/j.canlet.2023.216142
ISSN：

关键词： Cancer stem cells Triple-negative breast cancer Harmine Patient-derived organoids TGFβ receptor 1 inhibitor

摘要：
Triple-negative breast cancer (TNBC) has a poor prognosis due to the lack of specific and highly effective therapeutic agents. Cancer stem cells (CSCs) are one of the main factors contributing to TNBC relapse and metastasis. Therefore, targeting CSCs selectively with small molecules is a novel strategy for drug development. In this study, the natural product harmine (HM) was identified as a hit compound from 2632 natural product monomers based on phenotypic screening of a 2D assay and patient-derived organoid (PDO) model that was established from a patient who had multiple drug resistance and various visceral and contralateral breast metastases. Next, harmine was further modified and optimized to obtain a lead compound (YH677) with a tetrahydro-β-carboline scaffold. YH677 showed potent antiproliferative and antimigratory activities against several TNBC cell lines in vitro. In addition, YH677 inhibited epithelial mesenchymal transition (EMT) and stem cell marker expression in a dose-dependent manner. More importantly, YH677 suppressed breast cancer growth and metastasis in orthotopic, metastatic xenograft and patient-derived xenograft (PDX) models in vivo. Mechanistic studies showed that YH677 inhibits the expansion of CSCs by regulating the TGFβ/Smad signaling pathway. These preclinical data provide a basis for the development of YH677 as a lead compound for TNBC treatment.Copyright © 2023. Published by Elsevier B.V.

基金：
National Natural Science Foundation of China (No. 81904206, 82060663, 82260716); Key project at central government level: The ability establishment of sustainable use for valuable Chinese medicine resources (No.2060302).
语种：
外文
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PubmedID：
中科院(CAS)分区：
出版当年[2022]版：
大类 | 1 区 医学
小类 | 2 区 肿瘤学
最新[2025]版：
大类 | 1 区 医学
小类 | 2 区 肿瘤学
JCR分区：
出版当年[2021]版：
Q1 ONCOLOGY
最新[2023]版：
Q1 ONCOLOGY

影响因子： 最新[2023版] 最新五年平均 出版当年[2021版] 出版当年五年平均 出版前一年[2020版] 出版后一年[2022版]

第一作者：
第一作者机构： [1]National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China [4]Breast Department, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510120, China
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Zhang Yuzhu,Chen Jing,Mi Dazhao,et al.Discovery of YH677 as a cancer stemness inhibitor that suppresses triple-negative breast cancer growth and metastasis by regulating the TGF? signaling pathway[J].CANCER LETTERS.2023,560:doi:10.1016/j.canlet.2023.216142.
APA：
Zhang Yuzhu,Chen Jing,Mi Dazhao,Ling Jun,Li Huachao...&Huang Luqi.(2023).Discovery of YH677 as a cancer stemness inhibitor that suppresses triple-negative breast cancer growth and metastasis by regulating the TGF? signaling pathway.CANCER LETTERS,560,
MLA：
Zhang Yuzhu,et al."Discovery of YH677 as a cancer stemness inhibitor that suppresses triple-negative breast cancer growth and metastasis by regulating the TGF? signaling pathway".CANCER LETTERS 560.(2023)

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