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Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism
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Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism
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Journal Article
Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism
2018
Overview
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.
Publisher
National Academy of Sciences
Subject
/ Cell Hypoxia - radiation effects
/ Cell Proliferation - drug effects
/ Cell Proliferation - radiation effects
/ Female
/ Humans
/ Hypoxia
/ Lung Neoplasms - drug therapy
/ Lung Neoplasms - radiotherapy
/ Male
/ Mice
/ Mitochondria - radiation effects
/ NADH Dehydrogenase - antagonists & inhibitors
/ NADH Dehydrogenase - genetics
/ NADH-ubiquinone oxidoreductase
/ Oxygen
/ Phosphodiesterase Inhibitors - pharmacology
/ Radiation-Sensitizing Agents - pharmacology
/ Tumors
