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Significance Oxygen tension plays a critical role in the response to radiation therapy (RT). Here we show that hypoxic tumors can be sensitized to RT by targeting mitochondrial respiration. We identified the 150-year-old FDA-approved drug papaverine as a mitochondrial complex I inhibitor. A single dose of the drug prior to RT alleviates hypoxia in model tumors and strikingly enhances the response to RT. Well-oxygenated normal tissues are not radiosensitized. Removal of papaverine’s phosphodiesterase 10A inhibitory activity by structural modification has identified potentially safer generation of complex I-inhibiting radiosensitizers.

Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism