The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia

Area of Science:

• Oncology
• Biochemistry
• Pharmacology

Background:

• Tumour hypoxia is a major challenge in cancer therapy, leading to treatment resistance and poor patient outcomes.
• Identifying novel compounds that can alleviate tumour hypoxia is crucial for improving cancer treatment efficacy.

Purpose of the Study:

• To identify compounds that reduce oxygen consumption rate (OCR) as a strategy to target tumour hypoxia.
• To evaluate the efficacy of atovaquone, an anti-malarial drug, in reducing tumour hypoxia and enhancing cancer therapy.

Main Methods:

• High-throughput screening for compounds that decrease oxygen consumption rate (OCR).
• In vitro testing of atovaquone on various cancer cell lines and multicellular spheroids.
• In vivo studies using mouse xenograft models to assess atovaquone's effect on tumour hypoxia and growth, alone and in combination with radiation.

Main Results:

• Atovaquone demonstrated a rapid and significant reduction (over 80%) in OCR across diverse cancer cell lines at pharmacological concentrations.
• Atovaquone effectively eradicated hypoxia in FaDu, HCT116, and H1299 spheroids.
• In vivo, atovaquone reduced hypoxia in FaDu and HCT116 xenografts and significantly delayed tumour growth when combined with radiation.

Conclusions:

• Atovaquone inhibits mitochondrial complex III, leading to decreased OCR and reduced tumour hypoxia.
• Atovaquone shows potential as a therapeutic agent to overcome hypoxia-induced resistance in cancer.
• Clinical studies are underway to validate atovaquone's efficacy in patients, aiming to improve radiotherapy outcomes.