Itraconazole-Induced Inhibition on Human Esophageal Cancer Cell Growth Requires AMPK Activation

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Esophageal cancer remains a significant global health challenge with limited effective treatments.
• Antifungal drugs are being explored for novel anticancer properties.
• Understanding drug mechanisms of action is crucial for therapeutic development.

Purpose of the Study:

• To evaluate the efficacy of the antifungal drug itraconazole against human esophageal cancer cells.
• To elucidate the molecular mechanisms underlying itraconazole's anti-esophageal cancer activity.
• To assess the in vivo therapeutic potential of itraconazole in preclinical models.

Main Methods:

• In vitro studies using established and primary human esophageal cancer cell lines.
• Assessment of cell survival, proliferation, and cell death pathways (apoptosis, autophagy).
• In vivo xenograft models in SCID mice to evaluate tumor growth inhibition.

Main Results:

• Itraconazole significantly inhibited esophageal cancer cell survival and proliferation at μg/mL concentrations.
• Itraconazole-induced cytotoxicity was dependent on the activation of AMP-activated protein kinase (AMPK) signaling.
• The drug triggered AMPK-dependent autophagic cell death and inhibited receptor tyrosine kinases (RTKs), leading to reduced Akt activation.
• Oral itraconazole administration effectively suppressed tumor growth in vivo, with efficacy linked to AMPK activation.

Conclusions:

• Itraconazole demonstrates potent anti-esophageal cancer activity through AMPK pathway activation.
• The mechanism involves inducing autophagic cell death and RTK degradation.
• Itraconazole represents a promising therapeutic candidate for esophageal cancer treatment.