1. Syk Kinase Inhibitors Synergize with Artemisinins by Enhancing Oxidative Stress in Plasmodium Falciparum-Parasitized Erythrocytes
- Author
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Maria Carmina Pau, Antonella Pantaleo, Francesco Michelangelo Turrini, Patrizia Virdis, Claudio Fozza, Françoise Nepveu, Philip S. Low, Giuseppe Marchetti, Karine Reybier, Ioannis Tsamesidis, Università degli Studi di Sassari = University of Sassari [Sassari] (UNISS), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Purdue University [West Lafayette], and Università degli studi di Torino = University of Turin (UNITO)
- Subjects
0301 basic medicine ,Physiology ,[SDV]Life Sciences [q-bio] ,hemichromes ,Clinical Biochemistry ,Plasmodium falciparum ,Oxidative phosphorylation ,Pharmacology ,artemisinin derivatives ,medicine.disease_cause ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,parasitic diseases ,medicine ,oxidative stress ,Artemisinin ,Molecular Biology ,Hemichrome ,chemistry.chemical_classification ,reactive oxygen species ,Reactive oxygen species ,syk kinase inhibitors ,biology ,Chemistry ,lcsh:RM1-950 ,Cell Biology ,biology.organism_classification ,030104 developmental biology ,lcsh:Therapeutics. Pharmacology ,030220 oncology & carcinogenesis ,Toxicity ,Hemoglobin ,Oxidative stress ,medicine.drug - Abstract
International audience; Although artemisinin-based combination therapies (ACTs) treat Plasmodium falciparum malaria effectively throughout most of the world, the recent expansion of ACT-resistant strains in some countries of the Greater Mekong Subregion (GMS) further increased the interest in improving the effectiveness of treatment and counteracting resistance. Recognizing that (1) partially denatured hemoglobin containing reactive iron (hemichromes) is generated in parasitized red blood cells (pRBC) by oxidative stress, (2) redox-active hemichromes have the potential to enhance oxidative stress triggered by the parasite and the activation of artemisinin to its pharmaceutically active form, and (3) Syk kinase inhibitors block the release of membrane microparticles containing hemichromes, we hypothesized that increasing hemichrome content in parasitized erythrocytes through the inhibition of Syk kinase might trigger a virtuous cycle involving the activation of artemisinin, the enhancement of oxidative stress elicited by activated artemisinin, and a further increase in hemichrome production. We demonstrate here that artemisinin indeed augments oxidative stress within parasitized RBCs and that Syk kinase inhibitors further increase iron-dependent oxidative stress, synergizing with artemisinin in killing the parasite. We then demonstrate that Syk kinase inhibitors achieve this oxidative enhancement by preventing parasite-induced release of erythrocyte-derived microparticles containing redox-active hemichromes. We also observe that Syk kinase inhibitors do not promote oxidative toxicity to healthy RBCs as they do not produce appreciable amounts of hemichromes. Since some Syk kinase inhibitors can be taken daily with minimal side effects, we propose that Syk kinase inhibitors could evidently contribute to the potentiation of ACTs.
- Published
- 2020
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