Document Type

Article

Publication Date

10-16-2018

Publisher

National Academy of Sciences

Source Publication

Proceedings of the National Academy of Sciences (PNAS)

Source ISSN

0027-8424

Abstract

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.

Comments

Accepted version. Proceedings of the National Academy of Sciences (PNAS), Vol. 115, No. 42 (October 16, 2018): 10756-10761. DOI. © 2018 National Academy of Sciences. Used with permission.

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