Abstract 5841: Hypoxic tumors can be sensitized to radiation therapy by repurposing papaverine as an inhibitor of mitochondrial respiration
Authors: Benej Martin , Papandreou Ioanna , Hong Xiangqian , Yu Bing , Denko Nicholas 
Published: July 2017

Abstract
Tumor hypoxia is a characteristic feature of solid tumors. Low oxygen tension represents a barrier to effective radiation therapy because oxygen is required to fix the DNA damage induced by ionizing radiation. Many strategies have been proposed as a means to increase the radiosensitivity of hypoxic tumors but the clinical benefits have been disappointing. Finding an effective way to radiosensitize hypoxic tumors thus represents a major challenge for improving the current protocols for clinical radiation therapy.
Decreasing the demand for oxygen within the tumor has been proposed as a way to reduce hypoxia, as reduced demand could lead to increased tumor oxygenation prior to delivery of radiation. Although several compounds have been proposed based on this approach, the toxicity and/or required dose have proven to be a limitation of their potential clinical benefit. Papaverine is an opiate alkaloid that has been used in clinical practice for over 70 years as a smooth muscle relaxant. The drug has a long established safety profile, short biological half-life and most importantly, high potency in its off-target effect limiting mitochondrial oxygen consumption. We therefore hypothesized that papaverine could effectively radiosensitize hypoxic tumors by decreasing tumor hypoxia.
At clinically achievable concentrations in the low micromolar range, papaverine efficiently reduced the rate of oxygen consumption (OCR) in all tested cell lines in vitro. Within the first 30 minutes, 10 uM of the drug reduced the OCR by 30-40%. We identified the mechanism of OCR reduction as direct binding and inhibition of mitochondrial complex I, independent of the drug’s activity as a phosphodiesterase inhibitor. More importantly, a single dose of 2 mg/kg papaverine injected I.V. significantly increased tumor oxygenation in vivo by 1.2-1.3 fold in nude mice harboring EO771 and A549 xenografts. Because normal tissue is fully oxygenated, we found muscle oxygenation remained unchanged after drug delivery. Finally, 2 mg/kg papaverine injected 35 minutes prior to a single dose of irradiation resulted in a 2.0 fold relative growth delay in E0771 tumors compared to irradiation alone. In addition, in the more hypoxic A549 xenografts, the benefit provided by papaverine was a 3.0 fold relative growth delay. In conclusion, according to our data a single, clinically relevant dose of papaverine administered shortly before irradiation reduces tumor hypoxia and thus provides significant benefit over irradiation alone, strongly highlighting its potential to improve current strategies to enhance response to radiation therapy.
Citation Format: Martin Benej, Ioanna Papandreou, Xiangqian Hong, Bing Yu, Nicholas Denko. Hypoxic tumors can be sensitized to radiation therapy by repurposing papaverine as an inhibitor of mitochondrial respiration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5841. doi:10.1158/1538-7445.AM2017-5841