Cardioprotective Effect of Phase 3 Clinical Anticancer Agent, RRx-001, in Doxorubicin-Induced Acute Cardiotoxicity in Mice

Mol Pharm. 2019 Jul 1;16(7):2929-2934. doi: 10.1021/acs.molpharmaceut.9b00150. Epub 2019 Jun 3.


Anthracycline chemotherapy (e.g., doxorubicin or DOX) is associated with a cumulative dose-dependent cardiac dysfunction that may lead to congestive heart failure, which limits both its use and usefulness in the clinic. The cardiotoxicity may manifest acutely and/or months or years after treatment with doxorubicin has ended. Experimental and human data have demonstrated that angiotensin-converting enzyme/angiotensin-receptor antagonists mediate a cardioprotective effect against anthracycline toxicity. In this study, with the angiotensin receptor blocker, candesartan, as a positive control, we evaluated whether pretreatment with the hypoxic nitric oxide generating anticancer agent, RRx-001, could reduce acute DOX-induced cardiotoxicity. A total of 24 BALB/c mice were randomized for 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 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 (±d P/d tmax). Five days after doxorubicin injection, untreated (with RRx-001) mice displayed significantly impaired systolic (LVSP, -27%; d P/d tmax, -25%; left ventricular developed pressure (LVDP), +33%; P < 0.05) and global (stroke volume (SV), -52%; ejection fraction (EF), -20%; stroke work (SW), -62.5%; heart rate (HR), -18%; cardiac output (CO), -57%; mean blood arterial pressure (MAP), -30%; systemic vascular resistance (SVR), +20%; P < 0.05) LV functions when compared with the untreated (with RRx-001) group. In contrast, RRx-001-treated mice showed improved variables of systolic (LVSP, +27%; d P/d tmax, +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 functions compared with untreated doxorubicin mice. Similar to the positive control, candesartan, the cardiotoxic effects of DOX in mice were partially 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, may also have beneficial cardioprotective effects.

Keywords: RRx-001; angiotensin receptor blocker; anthracycline; cardioprotection; doxorubicin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Disease
  • Animals
  • Antibiotics, Antineoplastic / administration & dosage
  • Antibiotics, Antineoplastic / therapeutic use*
  • Azetidines / administration & dosage
  • Azetidines / therapeutic use*
  • Benzimidazoles / therapeutic use
  • Biphenyl Compounds
  • Blood Pressure / drug effects
  • Cardiomyopathies / chemically induced*
  • Cardiotonic Agents / administration & dosage
  • Cardiotonic Agents / therapeutic use*
  • Cardiotoxicity
  • Doxorubicin / administration & dosage
  • Doxorubicin / therapeutic use*
  • Doxorubicin / toxicity*
  • Heart Rate / drug effects
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms / drug therapy*
  • Nitro Compounds / administration & dosage
  • Nitro Compounds / therapeutic use*
  • Random Allocation
  • Stroke Volume / drug effects
  • Tetrazoles / therapeutic use


  • Antibiotics, Antineoplastic
  • Azetidines
  • Benzimidazoles
  • Biphenyl Compounds
  • Cardiotonic Agents
  • Nitro Compounds
  • RRx-001
  • Tetrazoles
  • Doxorubicin
  • candesartan