Early transcriptional response to chloroquine of the Plasmodium falciparum antioxidant defence in sensitive and resistant clones

Nogueira, Fátima; Díez, Amalia; Radfar, Azar; Pérez-Benavente, Susana; Rosário, Virgílio Estólio do; Puyet, Antonio; Bautista, José M.

doi:10.1016/j.actatropica.2010.01.013

Cited by 33 publications

(36 citation statements)

References 34 publications

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“…Overall, the data support an early transcriptional response to CQ-induced oxidative stress. [49] These properties help to reconcile the antagonism between CQ and each of MB, RF, and the artemisinins. The planar quinoline ring of CQ bearing a halogen or other electronegative group at C7 [40] may associate with systems incorporating electron-rich p systems such as LMB, VP, and FADH 2 .…”

Section: Discussionmentioning

confidence: 96%

A Partial Convergence in Action of Methylene Blue and Artemisinins: Antagonism with Chloroquine, a Reversal with Verapamil, and an Insight into the Antimalarial Activity of Chloroquine

Haynes

Cheu

et al. 2011

ChemMedChem

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Artemisinins rapidly oxidize leucomethylene blue (LMB) to methylene blue (MB); they also oxidize dihydroflavins such as the reduced conjugates RFH₂ of riboflavin (RF), and FADH₂ of the cofactor flavin adenine dinucleotide (FAD), to the corresponding flavins. Like the artemisinins, MB oxidizes FADH₂, but unlike artemisinins, it also oxidizes NAD(P)H. Like MB, artemisinins are implicated in the perturbation of redox balance in the malaria parasite by interfering with parasite flavoenzyme disulfide reductases. The oxidation of LMB by artemisinin is inhibited by chloroquine (CQ), an inhibition that is abruptly reversed by verapamil (VP). CQ also inhibits artemisinin-mediated oxidation of RFH₂ generated from N-benzyl-1,4-dihydronicotinamide (BNAH)-RF, or FADH₂ generated from NADPH or NADPH-Fre, an effect that is also modulated by verapamil. The inhibition likely proceeds by the association of LMB or dihydroflavin with CQ, possibly involving donor-acceptor or π complexes that hinder oxidation by artemisinin. VP competitively associates with CQ, liberating LMB or dihydroflavin from their respective CQ complexes. The observations explain the antagonism between CQ-MB and CQ-artemisinins in vitro, and are reconcilable with CQ perturbing intraparasitic redox homeostasis. They further suggest that a VP-CQ complex is a means by which VP reverses CQ resistance, wherein such a complex is not accessible to the putative CQ-resistance transporter (PfCRT).

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Section: Discussionmentioning

confidence: 96%

A Partial Convergence in Action of Methylene Blue and Artemisinins: Antagonism with Chloroquine, a Reversal with Verapamil, and an Insight into the Antimalarial Activity of Chloroquine

Haynes

Cheu

et al. 2011

ChemMedChem

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“…Studies on the effect of CQ treatment on the P. falciparum proteome (Prieto et al, 2008) and transcriptome (Gunasekera et al, 2003; Gunasekera et al, 2007) did not uncover clear evidence for an up-regulation of antioxidant defence systems. However, a recent study focusing specifically on antioxidant defence genes reported an up-regulation of certain transcripts, including that for pfmrp , after CQ treatment (2 h at the IC 50 concentration) in both CQS (3D7) and CQR (Dd2) parasites (Nogueira et al, 2010). …”

Section: Does Chloroquine Increase Oxidative Stress In the Parasite?mentioning

confidence: 99%

“…Nogueira et al (2010) reported that the glutathione system can respond to CQ treatment and that this response can differ between strains, as evidenced by the up-regulation of certain transcripts (including pfmrp in the 3D7 and Dd2 strains and pf γ- gcs and pfg6pd in the 3D7 strain) after a 2 h exposure of the parasites to CQ, at a concentration equivalent to the IC 50 of the strain in question. But does this response translate into an altered glutathione level, or modulate CQ susceptibility?…”

Section: A Link Between the Parasite’s Glutathione System And Chlomentioning

confidence: 99%

Degrees of chloroquine resistance in Plasmodium – Is the redox system involved?

Lehane

McDevitt

Kirk

et al. 2012

International Journal for Parasitology: Drugs and Drug Resistan

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Chloroquine (CQ) was once a very effective antimalarial drug that, at its peak, was consumed in the hundreds of millions of doses per year. The drug acts against the Plasmodium parasite during the asexual intraerythrocytic phase of its lifecycle. Unfortunately, clinical resistance to this drug is now widespread. Questions remain about precisely how CQ kills malaria parasites, and by what means some CQ-resistant (CQR) parasites can withstand much higher concentrations of the drug than others that also fall in the CQR category. In this review we investigate the evidence for and against the proposal that CQ kills parasites by generating oxidative stress. Further, we examine a long-held idea that the glutathione system of malaria parasites plays a role in CQ resistance. We conclude that there is strong evidence that glutathione levels modulate CQ response in the rodent malaria species P. berghei, but that a role for redox in contributing to the degree of CQ resistance in species infectious to humans has not been firmly established.

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“…As well as studies demonstrating essentiality of at least thioredoxin-dependent protection [10], [11], these systems may also protect the parasite from the actions of antimalarials that induce oxidative stress. For example, early transcriptional responses to CQ exposure include up-regulation of these systems [12]. Inhibition of glutathione synthesis in particular has also been shown to enhance the effect of chloroquine against P. berghei infections in mice [13], [14].…”

Section: Introductionmentioning

confidence: 99%

Treatment of Erythrocytes with the 2-Cys Peroxiredoxin Inhibitor, Conoidin A, Prevents the Growth of Plasmodium falciparum and Enhances Parasite Sensitivity to Chloroquine

et al. 2014

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The human erythrocyte contains an abundance of the thiol-dependant peroxidase Peroxiredoxin-2 (Prx2), which protects the cell from the pro-oxidant environment it encounters during its 120 days of life in the blood stream. In malarial infections, the Plasmodium parasite invades red cells and imports Prx2 during intraerythrocytic development, presumably to supplement in its own degradation of peroxides generated during cell metabolism, especially hemoglobin (Hb) digestion. Here we demonstrate that an irreversible Prx2 inhibitor, Conoidin A (2,3-bis(bromomethyl)-1,4-dioxide-quinoxaline; BBMQ), has potent cytocidal activity against cultured P. falciparum. Parasite growth was also inhibited in red cells that were treated with BBMQ and then washed prior to parasite infection. These cells remained susceptible to merozoite invasion, but failed to support normal intraerythrocytic development. In addition the potency of chloroquine (CQ), an antimalarial drug that prevents the detoxification of Hb-derived heme, was significantly enhanced in the presence of BBMQ. CQ IC50 values decreased an order of magnitude when parasites were either co-incubated with BBMQ, or introduced into BBMQ-pretreated cells; these effects were equivalent for both drug-resistant and drug-sensitive parasite lines. Together these results indicate that treatment of red cells with BBMQ renders them incapable of supporting parasite growth and increases parasite sensitivity to CQ. We also propose that molecules such as BBMQ that target host cell proteins may constitute a novel host-directed therapeutic approach for treating malaria.

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Early transcriptional response to chloroquine of the Plasmodium falciparum antioxidant defence in sensitive and resistant clones

Cited by 33 publications

References 34 publications

A Partial Convergence in Action of Methylene Blue and Artemisinins: Antagonism with Chloroquine, a Reversal with Verapamil, and an Insight into the Antimalarial Activity of Chloroquine

A Partial Convergence in Action of Methylene Blue and Artemisinins: Antagonism with Chloroquine, a Reversal with Verapamil, and an Insight into the Antimalarial Activity of Chloroquine

Degrees of chloroquine resistance in Plasmodium – Is the redox system involved?

Treatment of Erythrocytes with the 2-Cys Peroxiredoxin Inhibitor, Conoidin A, Prevents the Growth of Plasmodium falciparum and Enhances Parasite Sensitivity to Chloroquine

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