A novel lonidamine derivative targeting mitochondria to eliminate cancer stem cells by blocking glutamine metabolism

Qiang Wang; Shiyou Li; Chen Xu; Ao Hua; Chong Wang; Yuxuan Xiong; Qingyuan Deng; Xiang Chen; Tian Yang; Jiangling Wan; Ze-Yang Ding; Bi-Xiang Zhang; Xiangliang Yang; Zifu Li

doi:10.1016/j.phrs.2023.106740

A novel lonidamine derivative targeting mitochondria to eliminate cancer stem cells by blocking glutamine metabolism

Pharmacol Res. 2023 Apr:190:106740. doi: 10.1016/j.phrs.2023.106740. Epub 2023 Mar 21.

Authors

Qiang Wang¹, Shiyou Li¹, Chen Xu¹, Ao Hua¹, Chong Wang¹, Yuxuan Xiong¹, Qingyuan Deng¹, Xiang Chen¹, Tian Yang¹, Jiangling Wan¹, Ze-Yang Ding², Bi-Xiang Zhang², Xiangliang Yang³, Zifu Li⁴

Affiliations

¹ National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China.
² Hepatic Surgery Center and Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
³ National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China; Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China; Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, Wuhan 430074, PR China; GBA Research Innovation Institute for Nanotechnology, Guangdong 510530, PR China; Hubei Bioinformatics and Molecular Imaging Key Laboratory, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China.
⁴ National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China; Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China; Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, Wuhan 430074, PR China; Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Huazhong University of Science and Technology, Wuhan 430074, PR China; Hubei Bioinformatics and Molecular Imaging Key Laboratory, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China. Electronic address: zifuli@hust.edu.cn.

PMID: 36958408
DOI: 10.1016/j.phrs.2023.106740

Abstract

Cancer stem cells (CSCs) have been blamed as the main culprit of tumor initiation, progression, metastasis, chemoresistance, and recurrence. However, few anti-CSCs agents have achieved clinical success so far. Here we report a novel derivative of lonidamine (LND), namely HYL001, which selectively and potently inhibits CSCs by targeting mitochondria, with 380-fold and 340-fold lower IC₅₀ values against breast cancer stem cells (BCSCs) and hepatocellular carcinoma stem cells (HCSCs), respectively, compared to LND. Mechanistically, we reveal that HYL001 downregulates glutaminase (GLS) expression to block glutamine metabolism, blunt tricarboxylic acid cycle, and amplify mitochondrial oxidative stress, leading to apoptotic cell death. Therefore, HYL001 displays significant antitumor activity in vivo, both as a single agent and combined with paclitaxel. Furthermore, HYL001 represses CSCs of fresh tumor tissues derived from liver cancer patients. This study provides critical implications for CSCs biology and development of potent anti-CSCs drugs.

Keywords: Cancer stem cells; Glutamine metabolism; HYL001; Mitochondrial targeting.

Publication types

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

MeSH terms

Antineoplastic Agents* / metabolism
Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Cell Line, Tumor
Glutamine / metabolism
Humans
Liver Neoplasms* / drug therapy
Liver Neoplasms* / metabolism
Mitochondria / metabolism
Neoplastic Stem Cells

Substances

Antineoplastic Agents
lonidamine
Glutamine