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

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Cancer stem cells (CSCs) drive tumor initiation, progression, metastasis, chemoresistance, and recurrence.
• Existing anti-CSC agents have limited clinical success.
• Targeting CSCs is crucial for effective cancer treatment.

Purpose of the Study:

• To introduce a novel lonidamine (LND) derivative, HYL001, as a potent inhibitor of cancer stem cells (CSCs).
• To elucidate the mechanism of action of HYL001 in inhibiting CSCs.
• To evaluate the in vivo antitumor efficacy of HYL001.

Main Methods:

• Synthesis and characterization of HYL001, a novel LND derivative.
• In vitro assessment of HYL001's inhibitory effects on breast cancer stem cells (BCSCs) and hepatocellular carcinoma stem cells (HCSCs).
• Mechanistic studies involving glutaminase (GLS) expression, glutamine metabolism, tricarboxylic acid cycle, and mitochondrial oxidative stress.
• In vivo evaluation of HYL001's antitumor activity in preclinical models and patient-derived tumor tissues.

Main Results:

• HYL001 exhibits significantly higher potency against BCSCs and HCSCs compared to LND (380-fold and 340-fold lower IC50, respectively).
• HYL001 selectively targets mitochondria, downregulating GLS expression to disrupt glutamine metabolism and induce mitochondrial oxidative stress, leading to apoptosis.
• HYL001 demonstrates substantial in vivo antitumor activity as a single agent and in combination with paclitaxel, and represses CSCs in patient-derived liver cancer tissues.

Conclusions:

• HYL001 is a potent and selective inhibitor of cancer stem cells.
• The drug's mechanism involves targeting mitochondrial function and glutamine metabolism.
• HYL001 holds significant promise for the development of novel anti-cancer therapeutics targeting CSCs.