Journal
PHARMACOLOGICAL RESEARCH
Volume 190, Issue -, Pages -Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2023.106740
Keywords
HYL001; Cancer stem cells; Mitochondrial targeting; Glutamine metabolism
Categories
Ask authors/readers for more resources
In this study, a novel derivative of lonidamine (LND) called HYL001 was found to selectively and potently inhibit cancer stem cells (CSCs) by targeting mitochondria, with significantly lower IC50 values compared to LND. Mechanistically, HYL001 downregulates glutaminase expression to block glutamine metabolism, leading to apoptotic cell death. HYL001 also displays significant antitumor activity in vivo and represses CSCs in fresh tumor tissues from liver cancer patients.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available