Syk kinase inhibitors synergize with artemisinins by enhancing oxidative stress in plasmodium falciparum-parasitized erythrocytes

Ioannis Tsamesidis, Karine Reybier, Giuseppe Marchetti, Maria Carmina Pau, Patrizia Virdis, Claudio Fozza, Francoise Nepveu, Philip S. Low, Francesco Michelangelo Turrini, Antonella Pantaleo

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number753
Pages (from-to)1-21
Number of pages21
JournalAntioxidants
Volume9
Issue number8
DOIs
StatePublished - Aug 2020

Keywords

  • Artemisinin derivatives
  • Hemichromes
  • Oxidative stress
  • Plasmodium falciparum
  • Reactive oxygen species
  • Syk kinase inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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