Extracellular Heme Enhances the Antimalarial Activity of Artemisinin

Tangnitipong, Sunanta; Thaptimthong, Thitiporn; Srihirun, Sirada; Unchern, Supeenun; Kittikool, Dusadee; Udomsangpetch, Rachanee; Sibmooh, Nathawut

doi:10.1248/bpb.35.29

Cited by 8 publications

(4 citation statements)

References 29 publications

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“…In the absence of malaria parasites, free iron bioactivation of the endoperoxide bridge of artemisinin drugs can be used to modulate its effects (Conran, 2014;Krishna et al, 2004;Meshnick et al, 1989;Meshnick et al, 1993;Muhia et al, 1994;Tangnitipong et al, 2012). Delayed hemolysis in AS group follows a pattern similar to that reported in malaria infected persons (Arguin, 2014;Boillat et al, 2015;Chavada et al, 2015;Conran, 2014;Jauréguiberry et al, 2014;Kurth et al, 2016;Lee et al, 2015;Rehman et al, 2014;Rolling et al, 2015;WHO, 2013), although no anemia was recorded throughout this study.…”

Section: Discussionsupporting

confidence: 66%

Artemisinin-induced delayed hemolysis after administration of artesunate and artesunate-amodiaquine in malaria-free Wistar rats

et al. 2017

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Background: Hemolysis is common in malaria infection and during the course of treatment. Previous studies have reported delayed post-artemisinin hemolysis occurring in naïve and immune individuals treated with parenteral or oral artemisinin-derivatives. This study aims to understand if delayed hemolysis occurs in the absence of malaria parasites and the underlying mechanisms for the hemolytic effects after administration of two antimalarial drugs to malaria-free Wistar rats. Methods: Forty animals were randomized into 5 groups of eight animals each; they received 4 mg/kg artesunate for 7 days (AS), 4 mg/kg artesunate plus 10mg/kg amodiaquine for 3 days (ASQ), 10mg/kg amodiaquine for 3 days (AQ), distilled water [normal control], (Control) and 1mg/kg phenylhydrazine for 1 day to induce hemolysis (PHZ) groups respectively. Packed cell volume (PCV), white blood cell differential count and serum haptoglobin (Hpt) levels were determined in all groups on day 4 and 18 to detect hemolysis. Mean values were compared using t-test and ANOVA with p values <0.05 taken to be significantly different. Results: Post-treatment mean PCV on day 4 was significantly lower than day 18 in all groups except AS group which had similar PCV all through evaluation. Although AQ had lowest mean PCV on day 4, by day 18, mean PCV returned to normal and hpt levels was significantly higher than AS and ASQ groups (p<0.001). Hpt level (mean ± sem) for AS, ASQ, AQ, and control on day 18 were: 18.67 ± 0.004, 50.66 ± 0.014, 73.06 ± 0.003, and 74.13 ± 0.032 mg/dl respectively (p < 0.0001). On day 18, AS and ASQ had significantly lower Hpt level compared to day 4 (p <0.001). No neutropenia was observed during the study. Conclusion: Artesunate induces delayed hemolysis in malaria-free animals possibly through an oxidative toxic effect on the red blood cell membrane. Delayed post-treatment hemolysis was not observed with artesunateamodiaquine or amodiaquine alone.

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Section: Discussionsupporting

confidence: 66%

Artemisinin-induced delayed hemolysis after administration of artesunate and artesunate-amodiaquine in malaria-free Wistar rats

et al. 2017

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“…The malarial drug CQ manifests its potency by inhibiting heme to hemozoin conversion (22)(23)(24)(25)(26)(27)(28)(29). Hence, it enhances the intra-parasitic hemin load, which then results in parasite death (Ginsburg et al, 1998;Klonis et al, 2013;Meunier and Robert, 2010;Orjih, 1997;Orjih et al, 1994;Padmanaban and Rangarajan, 2000;Pandey et al, 1999;Tangnitipong et al, 2012). CQ treatment of parasites drives cellular death by the leakage of excessive hemin via the food vacuole membrane into the parasite cytosol (Surolia and Padmanaban, 1991), where PfRRS is resident.…”

Section: Discussionmentioning

confidence: 99%

Dimerization of Arginyl-tRNA Synthetase by Free Heme Drives Its Inactivation in Plasmodium falciparum

2016

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Excess cellular heme is toxic, and malaria parasites regulate its levels during hemoglobin digestion. Aminoacyl-tRNA synthetases are ubiquitous enzymes, and of these, arginyl-tRNA synthetase (RRS) is unique as its enzymatic product of charged tRNA is required for protein synthesis and degradation. We show that Plasmodium falciparum arginyl-tRNA synthetase (PfRRS) is an active, cytosolic, and monomeric enzyme. Its high-resolution crystal structure highlights critical structural differences with the human enzyme. We further show that hemin binds to and inhibits the aminoacylation activity of PfRRS. Hemin induces a dimeric form of PfRRS that is thus rendered enzymatically dead as it is unable to recognize its cognate tRNA(arg). Excessive hemin in chloroquine-treated malaria parasites results in significantly reduced charged tRNA(arg) levels, thus suggesting deceleration of protein synthesis. These data together suggest that the inhibition of Plasmodium falciparum arginyl-tRNA synthetase can now be synergized with existing antimalarials for more potent drug cocktails against malaria parasites.

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“…Furthermore, the inhibition of HO-1 by Sn-protoporphyrin increased PpIX accumulation and sensitivity of neoplasic cells, improving ALA-PDT treatment of cancer ( Frank et al., 2007 ). Additionally, the combination of extracellular heme with the antimalarial drug artemisinin enhanced the oxidative effect of heme ( Tangnitipong et al., 2012 ). Thus, endogenous stimulation of heme by ALA and exogenous addition of protoporphyrin IX and holotransferrin, improved cytotoxicity of dihydroartemisinin in cancer cells ( Zhang and Gerhard, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

Interactions between 4-aminoquinoline and heme: Promising mechanism against Trypanosoma cruzi

Lechuga

Borges

Calvet

et al. 2016

International Journal for Parasitology: Drugs and Drug Resistan

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Chagas disease is a neglected tropical disease caused by the flagellated protozoan Trypanosoma cruzi. The current drugs used to treat this disease have limited efficacy and produce severe side effects. Quinolines, nitrogen heterocycle compounds that form complexes with heme, have a broad spectrum of antiprotozoal activity and are a promising class of new compounds for Chagas disease chemotherapy. In this study, we evaluated the activity of a series of 4-arylaminoquinoline-3-carbonitrile derivatives against all forms of Trypanosoma cruzi in vitro. Compound 1g showed promising activity against epimastigote forms when combined with hemin (IC50<1 μM), with better performance than benznidazole, the reference drug. This compound also inhibited the viability of trypomastigotes and intracellular amastigotes. The potency of 1g in combination with heme was enhanced against epimastigotes and trypomastigotes, suggesting a similar mechanism of action that occurs in Plasmodium spp. The addition of hemin to the culture medium increased trypanocidal activity of analog 1g without changing the cytotoxicity of the host cell, reaching an IC50 of 11.7 μM for trypomastigotes. The mechanism of action was demonstrated by the interaction of compound 1g with hemin in solution and prevention of heme peroxidation. Compound 1g and heme treatment induced alterations of the mitochondrion-kinetoplast complex in epimastigotes and trypomastigotes and also, accumulation of electron-dense deposits in amastigotes as visualized by transmission electron microscopy. The trypanocidal activity of 4-aminoquinolines and the elucidation of the mechanism involving interaction with heme is a neglected field of research, given the parasite's lack of heme biosynthetic pathway and the importance of this cofactor for parasite survival and growth. The results of this study can improve and guide rational drug development and combination treatment strategies.

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Extracellular Heme Enhances the Antimalarial Activity of Artemisinin

Cited by 8 publications

References 29 publications

Artemisinin-induced delayed hemolysis after administration of artesunate and artesunate-amodiaquine in malaria-free Wistar rats

Artemisinin-induced delayed hemolysis after administration of artesunate and artesunate-amodiaquine in malaria-free Wistar rats

Dimerization of Arginyl-tRNA Synthetase by Free Heme Drives Its Inactivation in Plasmodium falciparum

Interactions between 4-aminoquinoline and heme: Promising mechanism against Trypanosoma cruzi

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