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

Abstract

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 (±dP/dt max). Five days after doxorubicin injection, untreated (with RRx-001) mice displayed significantly impaired systolic (LVSP, −27%; dP/dt max, −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%; dP/dt max, +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.

Pretreatment of ghrelin protects H9c2 cells against hypoxia/reoxygenation-induced cell death via PI3K/AKT and AMPK pathways

“…Therapies against ischemic injury, especially cardioprotective agents that are implemented before an ischemic event, have been considered as one of the main strategies for preventing MI. To date, multiple kinds of agents have been mentioned to have cardioprotective effects, such as pioglitazone [38], RRx-001 [39], 17b-Estradiol [40], as well as a natural agent like Tanshinone IIA [41]. Thus, more studies are needed to investigate the superiority and inferiority of ghrelin among these cardioprotective agents.…”

RRx-001: a chimeric triple action NLRP3 inhibitor, Nrf2 inducer, and nitric oxide superagonist

“…In addition to cancer ( 58 ), nitric oxide insufficiency/deficiency is a characteristic of several disease states ( 59 ) including pulmonary hypertension, hyperlipidemia, and non-alcoholic steatohepatitis (NASH) ( 60 ), COVID-19 ( 61 , 62 ), chronic kidney disease, myocardial infarction ( 63 ), cerebral malaria and stroke ( 64 ), ischemia reperfusion injury ( 65 ), hemorrhagic shock ( 66 ), and sickle cell disease ( 67 ) where RRx-001 has demonstrated activity, although not all this data is publicly available.…”

HERVs and Cancer—A Comprehensive Review of the Relationship of Human Endogenous Retroviruses and Human Cancers

“…Additional to the potential chemo-sensitizing action of the PURPL lncRNA, RRx-001, a novel anticancer drug in phase III clinical trials [ 229 ], displayed the induction of HERV-Fc2 env (HGCN: ERVFC1-1 ε ) and HERV-L LTRs in colon cancer cells resulting in an antiviral response, which sensitizes the cells to immuno-, radio-, and chemotherapy [ 230 ]. CRISPR-Cas9-mediated knockout of HERV-K (HML-2) env in DLD-1 colorectal cancer cells reduced migration, invasion, and tumor colonization and was sociated with nuclear protein-1 (NUPR1) reduction, indicating a potential connection [ 231 ].…”