Abstract 10336: Phase 3 Anticancer Agent, RRx-001, Ameliorates Hypoxia-Induced Pulmonary Hypertension

Abstract

Introduction: The hallmark features of pulmonary artery hypertension (PAH), for which hypoxia is a trigger, are vascular remodeling, elevated pulmonary blood pressure, oxidative stress, and right ventricular hypertrophy. RRx-001 is a minimally toxic Phase 3 anticancer agent with anti-oxidative, anti-inflammatory, nitric oxide-donating, and anti-proliferative properties. This study aimed to investigate the effect of RRx-001 on intermittent hypoxia-induced PAH in rats. Hypothesis: RRx-001 attenuates PAH Methods: Male Wistar rats (180-220 g) were divided into four groups (n=6 per group): normoxic control, hypoxic with vehicle treatment (2 weeks breathing an atmosphere containing 10% oxygen), hypoxic treated with oral endothelin-1 receptor inhibitor, bosentan, 50 mg/kg per day for 2 weeks during hypoxia and one intravenous dose of 5mg/kg RRx-001 given the day before the start of the hypoxia. After sacrifice, hearts and lungs were removed and harvested for analyses. Results: RRx-001 and bosentan, separately, significantly attenuated hypoxia-induced increases in right ventricular systolic pressure and right ventricular hypertrophy in PAH rats vs. vehicle. RRx-001 and bosentan, separately, also significantly decreased the thickening of pulmonary artery media and decreased the muscularization of pulmonary arterioles in PAH rats and the wall thickness/external diameter ratio of the pulmonary arteries vs. vehicle. Conclusions: RRx-001 significantly reduced right ventricular systolic pressure and pulmonary remodeling in a rat model of PAH, which potentially makes it a new therapeutic option for this dread disease. As a next step, combination of RRx-001 and bosentan will be attempted.