rrx-001 and Disease-Models--Animal

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

Topics: Animals; Azetidines; Blood Flow Velocity; Capillaries; Cricetinae; Disease Models, Animal; Male; Mesocricetus; Microcirculation; Nitro Compounds; Reperfusion Injury; Sodium Nitrite

The therapeutic potential of epi-immunotherapeutic anticancer agent RRx-001 in cancer has been validated with preclinical and clinical studies, since RRx-001 has successfully completed a phase 1 trial and multiple single-agent and combination phase 2 trials with preliminary evidence of promising activity are underway. Previous experimental work has implicated diverse anticancer mechanisms such as oxidative stress, ATP and NADPH depletion, anti-angiogenesis and epigenetic modulation in the overall antitumor effect of RRx-001. The hypothesis of this study was that the RRx-001 red blood cells are the essential and de facto intermediaries responsible for the reprograming of tumor behavior via transfer of their intracellular and membrane contents. To test this hypothesis, and thereby resolve the "black box" incompleteness in the continuity of the mechanism, the fate of red blood cells incubated with RRx-001 was explored in vitro and in vivo both in healthy animals and in tumor-bearing mice. The collective results establish that RRx-001-derivatized red blood cells are the critical "missing links" to explain the specificity and anticancer activity of RRx-001, including its immunomodulatory effects on tumor-associated macrophages. These experimental results delineate a novel erythrocyte-based mechanism without precedent in the annals of oncology and open the door to rational combination strategies with RRx-001 both in cancer therapy and beyond, particularly in disease states that affect red blood cell and vascular function such as malaria, leishmaniasis, sickle-cell disease and hemorrhagic shock.

Topics: Animals; Antineoplastic Agents; Azetidines; Disease Models, Animal; Erythrocytes; Macrophages; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Nitro Compounds; Random Allocation

The survival of malaria parasites, under substantial haem-induced oxidative stress in the red blood cells (RBCs) is dependent on the pentose phosphate pathway (PPP). The PPP is the only source of NADPH in the RBC, essential for the production of reduced glutathione (GSH) and for protection from oxidative stress. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, therefore, increases the vulnerability of erythrocytes to oxidative stress. In Plasmodium, G6PD is combined with the second enzyme of the PPP to create a unique bifunctional enzyme, named glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase (G6PD-6PGL). RRx-001 is a novel, systemically non-toxic, epigenetic anticancer agent currently in Phase 2 clinical development for multiple tumour types, with activity mediated through increased nitric oxide (NO) production and PPP inhibition. The inhibition of G6PD and NO overproduction induced by RRx-001 suggested its application in cerebral malaria (CM).. Plasmodium berghei ANKA (PbA) infection in C57BL/6 mice is an experimental model of cerebral malaria (ECM) with several similar pathological features to human CM. This study uses intravital microscopy methods with a closed cranial window model to quantify cerebral haemodynamic changes and leukocyte adhesion to endothelial cells in ECM.. RRx-001 had both single agent anti-parasitic activity and significantly increased the efficacy of artemether. In addition, RRx-001 preserved cerebral perfusion and reduced inflammation alone or combined with artemether. RRx-001's effects were associated with inhibition of PPP (G6PD and G6PD-6PGL) and by improvements in microcirculatory flow, which may be related to the NO donating properties of RRx-001.. The results indicate that RRx-001 could be used to potentiate the anti-malarial action of artemisinin, particularly on resistant strains, and to prevent infection.

Topics: Animals; Antimalarials; Artemether; Artemisinins; Azetidines; Carboxylic Ester Hydrolases; Disease Models, Animal; Drug Combinations; Glucosephosphate Dehydrogenase; Humans; Malaria, Cerebral; Mice; Mice, Inbred C57BL; Motor Activity; Nitro Compounds; Parasitemia; Plasmodium berghei