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. 2017 Jun;10(6):575-582.
doi: 10.1080/17474086.2017.1324779. Epub 2017 May 22.

The macrophage stimulating anti-cancer agent, RRx-001, protects against ischemia-reperfusion injury

Pedro Cabrales  1 , Scott Caroen  2 , Arnold Oronsky  3 , Corey Carter  4 , Jane Trepel  5 , Thomas Summers  4 , Tony Reid  6 , Neil Oronsky  6 , Michelle Lybeck  2 , Bryan Oronsky  2
Affiliations

The macrophage stimulating anti-cancer agent, RRx-001, protects against ischemia-reperfusion injury

Pedro Cabrales et al. Expert Rev Hematol. 2017 Jun.

Abstract

Background: RRx-001, a clinical macrophage-stimulating anti-cancer agent that also produces nitric oxide (NO) was studied in a model of ischemia-reperfusion injury.

Methods: The production of NO is dependent on the oxygen tension because nitric oxide synthases convert l-arginine to NO and l-citrulline in the presence of O2. Since the P450 enzymes, which metabolize nitrate esters such as nitroglycerin are dependent on oxygen, the generation of 'exogenous' NO is also sensitive to alterations in tissue PO2. I/R injury was studied in a hamster chamber window, with compression of the periphery of the window for 1 h to induce ischemia. Animals received RRx-001 (5 mg/kg) 24 h before ischemia and sodium nitrite (10 nmols/kg) was supplemented 10 min after the start of reperfusion. Vessel diameter, blood flow, adherent leukocytes, and functional capillary density were assessed by intravital microscopy at 0.5, 2, and 24 h following the release of the ischemia.

Results: The results demonstrated that, compared to control, RRx-001 preconditioning increased blood flow and functional capillary density, and preserved tissue viability in the absence of side effects over a sustained time period.

Conclusion: Thus, RRx-001 may serve as a long-lived protective agent during postsurgical restoration of flow and other ischemia-reperfusion associated conditions, increasing blood flow and functional capillary density as well as preserving tissue viability in the absence of side effects.

Keywords: Ischemia-reperfusion injury; RRx-001; functional capillary density; nitric oxide; oncology.

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Conflict of interest statement

Declaration of interest

B Oronsky is employed by EpicentRx. S Caroen is employed by EpicentRx. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Figures

Figure 1.
Figure 1.
Impact of leukocyte activation on blood flow and rheology in the microcirculation. In ischemia-reperfusion, peripheral resistance is elevated due to leukocyte obstruction due to pseudopod projections or cell adhesion to the vascular wall. (a) Normal Blood Flow. (b) Vessel during ischemia-reperfusion. (c) Vessel during ischemia reperfusion, treated with nitric oxide.
Figure 2.
Figure 2.
Experimental Model.
Figure 3.
Figure 3.
Arteriolar diameter and blood flow following the release of the ischemia. *p < 0.05 compared to control.
Figure 4.
Figure 4.
Functional capillary density (FCD) and immobilized leukocytes following the release of the ischemia. †, p < 0.05 compared to control.
Figure 5.
Figure 5.
Immobilized leukocytes following the release of the ischemia. †, p < 0.05 compared to control.
Figure 6.
Figure 6.
Tissue viability 24 following the release of the ischemia. **p < 0.05 for both the number of apoptotic and necrotic in the RRx-001 treatment group compared to control.
Figure 7.
Figure 7.
RRx-001 binds to a thiol residue on βeta-Cys-93.
See this image and copyright information in PMC

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