M. Benej, Xiangqian Hong, Sandip Vibhute
Sep 10, 2018
Citations
7
Influential Citations
114
Citations
Quality indicators
Journal
Proceedings of the National Academy of Sciences
Abstract
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. Tumor hypoxia reduces the effectiveness of radiation therapy by limiting the biologically effective dose. An acute increase in tumor oxygenation before radiation treatment should therefore significantly improve the tumor cell kill after radiation. Efforts to increase oxygen delivery to the tumor have not shown positive clinical results. Here we show that targeting mitochondrial respiration results in a significant reduction of the tumor cells’ demand for oxygen, leading to increased tumor oxygenation and radiation response. We identified an activity of the FDA-approved drug papaverine as an inhibitor of mitochondrial complex I. We also provide genetic evidence that papaverine’s complex I inhibition is directly responsible for increased oxygenation and enhanced radiation response. Furthermore, we describe derivatives of papaverine that have the potential to become clinical radiosensitizers with potentially fewer side effects. Importantly, this radiosensitizing strategy will not sensitize well-oxygenated normal tissue, thereby increasing the therapeutic index of radiotherapy.