New antimalarial indolone-N-oxides, generating radical species, destabilize the host cell membrane at early stages of Plasmodium falciparum growth: Role of band 3 tyrosine phosphorylation

Antonella Pantaleo, Emanuela Ferru, Rosa Vono, Giuliana Giribaldi, Omar Lobina, Françoise Nepveu, Hany Ibrahim, Jean Pierre Nallet, Franco Carta, Franca Mannu, Proto Pippia, Estela Campanella, Philip S. Low, Francesco Turrini

Research output: Contribution to journalArticlepeer-review

Abstract

Although indolone-N-oxide (INODs) genereting long-lived radicals possess antiplasmodial activity in the low-nanomolar range, little is known about their mechanism of action. To explore the molecular basis of INOD activity, we screened for changes in INOD-treated malaria-infected erythrocytes (Pf-RBCs) using a proteomics approach. At early parasite maturation stages, treatment with INODs at their IC 50 concentrations induced a marked tyrosine phosphorylation of the erythrocyte membrane protein band 3, whereas no effect was observed in control RBCs. After INOD treatment of Pf-RBCs we also observed: (i) accelerated formation of membrane aggregates containing hyperphosphorylated band 3, Syk kinase, and denatured hemoglobin; (ii) dose-dependent release of microvesicles containing the membrane aggregates; (iii) reduction in band 3 phosphorylation, Pf-RBC vesiculation, and antimalarial effect of INODs upon addition of Syk kinase inhibitors; and (iv) correlation between the IC 50 and the INOD concentrations required to induce band 3 phosphorylation and vesiculation. Together with previous data demonstrating that tyrosine phosphorylation of oxidized band 3 promotes its dissociation from the cytoskeleton, these results suggest that INODs cause a profound destabilization of the Pf-RBC membrane through a mechanism apparently triggered by the activation of a redox signaling pathway rather than direct oxidative damage.

Original languageEnglish
Pages (from-to)527-536
Number of pages10
JournalFree Radical Biology and Medicine
Volume52
Issue number2
DOIs
Publication statusPublished - Jan 15 2012

Keywords

  • Band 3
  • Free radicals
  • Oxidative damage
  • Plasmodium falciparum
  • Red blood cells
  • Tyrosine phosphorylation

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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