Pharmacological Regulation of Tumor Hypoxia in Model Murine Tumors and Spontaneous Canine Tumors

SIMPLE SUMMARY: Tumor hypoxia is a state of low oxygen tension typically occurring in most solid tumors because the oxygen supply does not meet the metabolic demand of the tissue. Hypoxia has been associated with increased resistance to anti-cancer therapy for decades. Reducing oxygen demand with therapeutic targeting of mitochondrial oxidative metabolism can mitigate tumor hypoxia. Here we show that pharmacological regulation of mitochondrial metabolism has a direct impact on the levels of tumor hypoxia in murine tumor models and spontaneous canine soft tissue sarcomas. ABSTRACT: Background: Hypoxia is found in many solid tumors and is associated with increased disease aggressiveness and resistance to therapy. Reducing oxygen demand by targeting mitochondrial oxidative metabolism is an emerging concept in translational cancer research aimed at reducing hypoxia. We have shown that the U.S. Food and Drug Administration (FDA)-approved drug papaverine and its novel derivative SMV-32 are potent mitochondrial complex I inhibitors. Methods: We used a dynamic in vivo luciferase reporter system, pODD-Luc, to evaluate the impact of pharmacological manipulation of mitochondrial metabolism on the levels of tumor hypoxia in transplanted mouse tumors. We also imaged canine patients with blood oxygen level-dependent (BOLD) MRI at baseline and one hour after a dose of 1 or 2 mg/kg papaverine. Results: We showed that the pharmacological suppression of mitochondrial oxygen consumption (OCR) in tumor-bearing mice increases tumor oxygenation, while the stimulation of mitochondrial OCR decreases tumor oxygenation. In parallel experiments in a small series of spontaneous canine sarcomas treated at The Ohio State University (OSU) Veterinary Medical Center, we observed a significant increase in BOLD signals indicative of an increase in tumor oxygenation of up to 10–50 mm HgO(2). Conclusion: In both transplanted murine tumors and spontaneous canine tumors we found that decreasing mitochondrial metabolism can decrease tumor hypoxia, potentially offering a therapeutic advantage.