title: From METS to malaria: RRx-001, a multi-faceted anticancer agent with activity in cerebral malaria.
abstract: BACKGROUND
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Bioengineering, University of California, 9500 Gilman Dr., La Jolla, San Diego, CA, 92093-0412, USA. ozlemyalcin@ku.edu.tr.|School of Medicine, Koç University, Sariyer, Istanbul, Turkey. ozlemyalcin@ku.edu.tr.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Yalcin
authors.affiliation: EpicentRx Inc, Mountain View, CA, USA. boronsky@epicentrx.com.
authors.forename: Bryan
authors.initials: B
authors.lastname: Oronsky
authors.affiliation: Center for Malaria Research, La Jolla Bioengineering Institute, San Diego, CA, USA. lcarvalho@ljbi.org.|Laboratory of Malaria Research, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil. lcarvalho@ljbi.org.
authors.forename: Leonardo J M
authors.initials: LJ
authors.lastname: Carvalho
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, CA, USA. frackaku@chori.org.
authors.forename: Frans A
authors.initials: FA
authors.lastname: Kuypers
authors.affiliation: EpicentRx Inc, Mountain View, CA, USA. jscicinski@epicentrx.com.
authors.forename: Jan
authors.initials: J
authors.lastname: Scicinski
authors.affiliation: Department of Bioengineering, University of California, 9500 Gilman Dr., La Jolla, San Diego, CA, 92093-0412, USA. pcabrales@ucsd.edu.
authors.forename: Pedro
authors.initials: P
authors.lastname: Cabrales
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D000077549:Artemether; D037621:Artemisinins / Q000627:therapeutic use*; D001384:Azetidines / Q000627:therapeutic use*; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D004195:Disease Models, Animal; D004338:Drug Combinations; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D006801:Humans; D016779:Malaria, Cerebral / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D009574:Nitro Compounds / Q000627:therapeutic use*; D018512:Parasitemia / Q000188:drug therapy; D010962:Plasmodium berghei / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D001384:Azetidines; D004338:Drug Combinations; D009574:Nitro Compounds; C577469:RRx-001; D000077549:Artemether; D005954:Glucosephosphate Dehydrogenase; D002265:Carboxylic Ester Hydrolases; C022363:6-phosphogluconolactonase