Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism. Proc Natl Acad Sci U S A 2018 Oct 16;115(42):10756-10761
Date
09/12/2018Pubmed ID
30201710Pubmed Central ID
PMC6196495DOI
10.1073/pnas.1808945115Scopus ID
2-s2.0-85054969348 (requires institutional sign-in at Scopus site) 117 CitationsAbstract
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.
Author List
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 NCAuthor
Bing Yu PH.D. Assistant Professor of Biomedical Engineering in the Biomedical Engineering department at Marquette UniversityMESH terms used to index this publication - Major topics in bold
AnimalsCRISPR-Cas Systems
Cell Hypoxia
Cell Proliferation
Electron Transport Complex I
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
