Abstract
BackgroundThe 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).MethodsPlasmodium 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.ResultsRRx-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.ConclusionThe results indicate that RRx-001 could be used to potentiate the anti-malarial action of artemisinin, particularly on resistant strains, and to prevent infection.
Highlights
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)
RRx-001 is a potent inhibitor of Glucose-6phosphate dehydrogenase (G6PD) Given the tropism of RRx-001 for the RBC and the dependence of the malaria parasite on the PPP, the effects of RRx-001 on 6GPD of RBCs, infected RBCs, and parasites were initially explored (Fig. 1c)
Infected RBCs presented a significantly increased glucose metabolism compared to uninfected RBCs (Fig. 1)
Summary
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). Glucose-6phosphate dehydrogenase (G6PD) deficiency, increases the vulnerability of erythrocytes to oxidative stress. 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. Its pathogenesis is quite complex and involves a cascading interaction between the parasitized red blood cells (RBCs), The malarial parasitic protozoan, Plasmodium falciparum, inextricably linked with humanity since the dawn of time and the evolutionary driving force behind sickle cell disease, thalassaemias and G6PD deficiency, and responsible for more than a million deaths every year, remains an elusive therapeutic target [6]. An increasing prevalence of resistance to anti-malarial drugs and a relative dearth of active agents compound the problem: adjuvant therapy clinical trials with mannitol, steroids, antipyretics, antiseizure control, pentoxifylline, and deferoxamine, among others, have yielded disappointing results [7]
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