Wang Qiang, Li Shiyou, Xu Chen, Hua Ao, Wang Chong, Xiong Yuxuan, Deng Qingyuan, Chen Xiang, Yang Tian, Wan Jiangling, Ding Ze-Yang, Zhang Bi-Xiang, Yang Xiangliang, Li Zifu
National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China.
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.
Pharmacol Res. 2023 Apr;190:106740. doi: 10.1016/j.phrs.2023.106740. Epub 2023 Mar 21.
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 IC 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.
癌症干细胞（CSCs）被认为是肿瘤起始、进展、转移、化疗耐药及复发的主要元凶。然而，到目前为止，几乎没有抗CSCs药物取得临床成功。在此，我们报告了一种氯尼达明（LND）的新型衍生物，即HYL001，它通过靶向线粒体选择性且强效地抑制CSCs，与LND相比，对乳腺癌干细胞（BCSCs）和肝癌干细胞（HCSCs）的半数抑制浓度（IC）值分别低380倍和340倍。从机制上来说，我们发现HYL001下调谷氨酰胺酶（GLS）表达以阻断谷氨酰胺代谢，减弱三羧酸循环，并放大线粒体氧化应激，从而导致细胞凋亡死亡。因此，HYL001无论是作为单一药物还是与紫杉醇联合使用，在体内均显示出显著的抗肿瘤活性。此外，HYL001可抑制源自肝癌患者的新鲜肿瘤组织中的CSCs。本研究为CSCs生物学及强效抗CSCs药物的开发提供了关键启示。
