Abstract 2927: Papaverine and its novel derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism
Authors: Benej Martin , Hong Xiangqian , Vibhute Sandip , Scott Sabina , Wu Jinghai , Graves Edward , Le Quynh-Thu , Koong Albert C. , Giaccia Amato J. , Chen Ching-Shih , Yu Bing , Papandreou Ioanna , Denko Nicholas C. 
Published: August 2019

Radiation therapy is a standard type of treatment modality used to achieve local control in more than 50% of all cancer patients. However, tumor hypoxia reduces the effectiveness of radiation therapy by limiting the biologically effective dose. Limited distribution of oxygen is a direct consequence of abnormalities in vascular structure and angiogenesis that fails to provide sufficient oxygen to meet the demands of metabolically hyperactive cancer cells. An acute increase in tumor oxygenation prior to radiation treatment should therefore significantly improve the tumor cell kill after radiation. Nonetheless, therapeutic efforts to increase oxygen delivery to the tumor have not shown positive clinical results to this day. We have taken an alternative route by targeting the demand for oxygen rather than its supply. In the cell, mitochondrial respiration is the major oxygen-consuming process. We show that pharmacological inhibition of mitochondrial oxygen consumption (OCR) temporarily reduces the tumor cells’ demand for oxygen leading to increased tumor oxygenation and enhanced radiation response. We identified a previously unrecognized activity of the FDA-approved drug papaverine as an inhibitor of mitochondrial complex I. In vivo, a single clinically achievable dose of papaverine increased tumor, but not normal tissue oxygenation within 45 minutes and strikingly enhanced tumor response to radiation therapy in both ortho- and heterotopic rodent tumor models. Moreover, our GI tract studies show that this can be achieved without exacerbating normal tissue toxicity, as papaverine does not radiosensitize hypoxic normal tissues. Papaverine is an ergot alkaloid originally isolated from Papaver somniferum in 1848. It was used for decades as smooth muscle relaxant to treat vasospasms and erectile dysfunction. Its vascular effects were believed to be mediated by its ability to inhibit phosphodiesterase 10A (PDE10A). We provide genetic evidence that papaverine’s complex I inhibition, not its activity as a PDE10A inhibitor is directly responsible for increased oxygenation and enhanced radiation response. Furthermore, we describe novel derivatives of papaverine that have the potential to become a new generation of clinical radiosensitizers with potentially fewer side effects. Papaverine has a short half-life of 90-120 minutes, is cell-permeable, reversible and quickly cleared from the patient. In vitro, all 28 cancer and normal cell lines tested were sensitive to papaverine regardless of their oncogenic landscape, suggesting possible application for a broad spectrum of cancers that depends primarily on their level of hypoxia. In conclusion, PPV or one of its novel derivatives appear to be ideal candidates for clinical radiosensitization, applicable primarily in cancers where local control increases the overall survival.

Citation Format: Martin Benej, Xiangqian Hong, Sandip Vibhute, Sabina Scott, Jinghai Wu, Edward Graves, Quynh-Thu Le, Albert C. Koong, Amato J. Giaccia, Ching-Shih Chen, Bing Yu, Ioanna Papandreou, Nicholas C. Denko. Papaverine and its novel derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2927.