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

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• 作者：Antonella Pantaleo^a ; ¹ ; ^{apantaleo@uniss.it} ; Emanuela Ferru^b ; ¹ ; Rosa Vono^b ; Giuliana Giribaldi^b ; Omar Lobina^b ; Franç ; oise Nepveu^c ; ^d ; Hany Ibrahim^c ; ^d ; Jean-Pierre Nallet^e ; Franco Carta^f ; Franca Mannu^f ; Proto Pippia^a ; Estela Campanella^g ; Philip S. Low^g ; Francesco Turrini^b
• 关键词：Pf-RBC ; Plasmodium falciparum red blood cell ; INOD ; indolone-N-oxide derivative ; G6PD ; glucose-6-phosphate dehydrogenase
• 刊名：Free Radical Biology and Medicine
• 出版年：2012
• 出版时间：15 January 2012
• 年：2012
• 卷：52
• 期：2
• 页码：527-536
• 全文大小：1080 K

文摘

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 IC₅₀ 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 IC₅₀ 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.