Preclinical evidence of synergism between atovaquone and chemotherapy by AMPK-dependent mitochondrial dysfunction

Area of Science:

• Oncology
• Pharmacology
• Mitochondrial Biology

Background:

• Chemoresistance in lung cancer often correlates with increased mitochondrial activity.
• Atovaquone, an established anti-malarial, functions as a mitochondrial inhibitor.

Purpose of the Study:

• To investigate the potential repurposing of atovaquone for treating non-small cell lung cancer (NSCLC).
• To evaluate atovaquone's efficacy in overcoming chemoresistance and its synergistic effects with chemotherapy.

Main Methods:

• In vitro studies using NSCLC cell lines to assess proliferation, colony formation, and survival.
• In vivo studies using NSCLC xenograft mouse models.
• Mechanistic studies involving mitochondrial complex III inhibition, oxygen consumption assays, and analysis of AMPK/mTOR signaling pathways.

Main Results:

• Atovaquone demonstrated significant inhibition of NSCLC cell proliferation, colony formation, and survival at clinically achievable doses.
• Atovaquone exhibited synergistic effects with carboplatin in both in vitro and in vivo NSCLC models.
• Atovaquone disrupts mitochondrial function by inhibiting complex III, leading to AMPK activation and mTOR inhibition, which is crucial for its anti-cancer activity.

Conclusions:

• Atovaquone is a promising candidate for NSCLC treatment, particularly for overcoming chemoresistance.
• Targeting mitochondrial function represents a viable therapeutic strategy to improve chemosensitivity in NSCLC.
• The synergistic action of atovaquone with carboplatin warrants further clinical investigation.