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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.

Original publication

DOI

10.1073/pnas.1808945115

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

16/10/2018

Volume

115

Pages

10756 - 10761

Keywords

hypoxia, metabolism, mitochondria, radiosensitization, Animals, CRISPR-Cas Systems, Cell Hypoxia, Cell Proliferation, Female, Humans, Lung Neoplasms, Male, Mice, Mice, Inbred C57BL, Mitochondria, NADH Dehydrogenase, Oxygen, Papaverine, Phosphodiesterase Inhibitors, Radiation Tolerance, Radiation-Sensitizing Agents, Tumor Cells, Cultured, Xenograft Model Antitumor Assays