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.
journal_name
Proc Natl Acad Sci U S Aauthors
Benej M,Hong X,Vibhute S,Scott S,Wu J,Graves E,Le QT,Koong AC,Giaccia AJ,Yu B,Chen CS,Papandreou I,Denko NCdoi
10.1073/pnas.1808945115subject
Has Abstractpub_date
2018-10-16 00:00:00pages
10756-10761issue
42eissn
0027-8424issn
1091-6490pii
1808945115journal_volume
115pub_type
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