Abstract 12627: Clinical Anticancer Agent, RRx-001, protects From Doxorubicin-Induced Cardiotoxicity
Introduction: Anthracycline (ANT) chemotherapy (e.g., doxorubicin or DOX) is associated with dose-dependent cardiac dysfunction, leading to congestive heart failure, and therefore has limited clinical use. The cardiotoxicity may manifest acutely and/or months or years after treatment. Current clinically used therapies include angiotensin-converting enzyme/angiotensin-receptor antagonists (ARB) which are cardioprotective against ANT toxicity.
Hypothesis: Pre-treatment with the hypoxic nitric oxide generating anticancer agent, RRx-001, mitigates acute DOX-induced cardiotoxicity. Candesartan (ARB) was used as a positive control.
Methods: 24 BALB/c mice were randomized to prophylactic treatment with vehicle, RRx-001, candesartan or no-intervention control. Within each of the three intervention arms, mice received treatment with DOX. Murine pressure-volume (PV) analysis was performed with microconductance catheters to characterize the degree of cardiovascular dysfunction within each group. The following hemodynamic parameters were monitored: left ventricular systolic pressure (LVSP), heart rate, and maximal rate of increase of left ventricular pressure (±dP/dt max).
Results: Five days after doxorubicin injection, untreated mice displayed significantly impaired systolic (LVSP, –27%; dP/dtmax, –25%; LVDP, + 33%; P < 0.05) and global (SV, –52%; EF-20%; SW-62.5%; HR, –18%; CO, –57%; MAP-30%; SVR+20% P < 0.05) LV function when compared with the untreated group. In contrast, RRx-001-treated mice showed improved variables of systolic (LVSP, +27%; dP/dtmax, +25%; LVDP, -33%; P < 0.05) and global (SV, +52%; EF+20%; SW+62.5%; HR, +18%; CO, +57%; MAP+30%; SVR-20% P < 0.05) LV function compared to untreated controls. RRx-001 treated mice demonstrated improved parameters of LV function compared to candesartan, though the differences were not significant.
Conclusions: Similar to the positive control, candesartan, the cardiotoxic effects of DOX in mice were attenuated by the prophylactic administration of RRx-001. These results suggest that RRx-001, as a multifunctional anticancer agent, which sensitizes cancer cells to the cytotoxic effects of chemotherapy and radiation, with beneficial cardioprotective effects.
Author Disclosures: B. Oronsky: Employment; Significant; ownership interest in EpicentRx, Inc. J. Scicinski: Employment; Significant; ownership interest in EpicentRx. P. Cabrales: None.
- © 2016 by American Heart Association, Inc.