Oxidation of Erythrocytes Enhance the Production of Reactive Species in the Presence of Artemisinins

Tsamesidis, Ioannis; Pério, Pierre; Pantaleo, Antonella; Reybier, Karine

doi:10.3390/ijms21134799

Cited by 14 publications

(13 citation statements)

References 58 publications

(72 reference statements)

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“…Based on this pathway, the activation and/or the potency of artemisinins must depend on the abundance of HMCs in parasitized RBCs, which in turn will depend on the ability of the parasite to eliminate these HMCs in discharged microparticles. The release of MPs containing hemichromes was already described in oxidized erythrocytes [70,71], in parasitized RBCs [20,44], and in different hematological diseases characterized by hemichrome formation such as thalassemias and G6PD-deficient RBCs following oxidant treatment [39,66]. Supporting the proposed mechanism of action, iron chelators and ROS scavengers suppressed the anti-plasmodial activity of the Syk inhibitor + artemisinin treatment.…”

Section: Discussionmentioning

confidence: 71%

Syk Kinase Inhibitors Synergize with Artemisinins by Enhancing Oxidative Stress in Plasmodium falciparum-Parasitized Erythrocytes

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 71%

Syk Kinase Inhibitors Synergize with Artemisinins by Enhancing Oxidative Stress in Plasmodium falciparum-Parasitized Erythrocytes

et al. 2020

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“…We thus moved to intact cells, in which the detection of superoxide, the primary radical formed under the menadione metabolism, was measured by LC-MS for the 3 cell lines. These sets of experiments were based on the use of dihydroethidium (DHE) which gives a specific adduct, the 2-hydroxyethidium (2OH-E + ) after reaction with superoxide ( Zielonka et al, 2008 ; Kalyanaraman et al, 2017 ; Tsamesidis et al, 2020a ; Tsamesidis et al, 2020b ) that can be detected by MS (m/z 330). The three SH-SY5Y lines were incubated for 30 min in the presence of BNAH (25 μM), UDPGA (2 mM), DHE (10 μM) and menadione (25 μM).…”

Section: Resultsmentioning

confidence: 99%

Association of NQO2 With UDP-Glucuronosyltransferases Reduces Menadione Toxicity in Neuroblastoma Cells

Chhour

Pério

Gayon³

et al. 2021

Front. Pharmacol.

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The balance between detoxification and toxicity is linked to enzymes of the drug metabolism Phase I (cytochrome P450 or oxidoreductases) and phase II conjugating enzymes (such as the UGTs). After the reduction of quinones, the product of the reaction, the quinols—if not conjugated—re-oxidizes spontaneously to form the substrate quinone with the concomitant production of the toxic reactive oxygen species (ROS). Herein, we documented the modulation of the toxicity of the quinone menadione on a genetically modified neuroblastoma model cell line that expresses both the quinone oxidoreductase 2 (NQO2, E.C. 1.10.5.1) alone or together with the conjugation enzyme UDP-glucuronosyltransferase (UGT1A6, E.C. 2.4.1.17), one of the two UGT isoenzymes capable to conjugate menadione. As previously shown, NQO2 enzymatic activity is concomitant to massive ROS production, as previously shown. The quantification of ROS produced by the menadione metabolism was probed by electron-paramagnetic resonance (EPR) on cell homogenates, while the production of superoxide was measured by liquid chromatography coupled to mass spectrometry (LC-MS) on intact cells. In addition, the dysregulation of the redox homeostasis upon the cell exposure to menadione was studied by fluorescence measurements. Both EPR and LCMS studies confirmed a significant increase in the ROS production in the NQO2 overexpressing cells due to the fast reduction of quinone into quinol that can re-oxidize to form superoxide radicals. However, the effect of NQO2 inhibition was drastically different between cells overexpressing only NQO2 vs. both NQO2 and UGT. Whereas NQO2 inhibition decreases the amount of superoxide in the first case by decreasing the amount of quinol formed, it increased the toxicity of menadione in the cells co-expressing both enzymes. Moreover, for the cells co-expressing QR2 and UGT the homeostasis dysregulation was lower in presence of menadione than for the its counterpart expressing only QR2. Those results confirmed that the cooperation of the two enzymes plays a fundamental role during the cells’ detoxification process. The fluorescence measurements of the variation of redox homeostasis of each cell line and the detection of a glucuronide form of menadiol in the cells co-expressing NQO2 and UGT1A6 enzymes further confirmed our findings.

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“…To oxidize the RBCs, they were suspended at a hematocrit of 30% and incubated with 1 mM phenylhydrazine (PHZ) at 37 • C for 4 h, as previously described [39]. Each reaction was terminated by three washes with phosphate buffer saline containing glucose (PBS-glucose).…”

Section: Oxidation Of Rbcsmentioning

confidence: 99%

In Vitro and In Silico Antimalarial Evaluation of FM-AZ, a New Artemisinin Derivative

et al. 2022

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Artemisinin-based Combination Therapies (ACTs) are currently the frontline treatment against Plasmodium falciparum malaria, but parasite resistance to artemisinin (ART) and its derivatives, core components of ACTs, is spreading in the Mekong countries. In this study, we report the synthesis of several novel artemisinin derivatives and evaluate their in vitro and in silico capacity to counteract Plasmodium falciparum artemisinin resistance. Furthermore, recognizing that the malaria parasite devotes considerable resources to minimizing the oxidative stress that it creates during its rapid consumption of hemoglobin and the release of heme, we sought to explore whether further augmentation of this oxidative toxicity might constitute an important addition to artemisinins. The present report demonstrates, in vitro, that FM-AZ, a newly synthesized artemisinin derivative, has a lower IC50 than artemisinin in P. falciparum and a rapid action in killing the parasites. The docking studies for important parasite protein targets, PfATP6 and PfHDP, complemented the in vitro results, explaining the superior IC50 values of FM-AZ in comparison with ART obtained for the ART-resistant strain. However, cross-resistance between FM-AZ and artemisinins was evidenced in vitro.

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Oxidation of Erythrocytes Enhance the Production of Reactive Species in the Presence of Artemisinins

Cited by 14 publications

References 58 publications

Syk Kinase Inhibitors Synergize with Artemisinins by Enhancing Oxidative Stress in Plasmodium falciparum-Parasitized Erythrocytes

Syk Kinase Inhibitors Synergize with Artemisinins by Enhancing Oxidative Stress in Plasmodium falciparum-Parasitized Erythrocytes

Association of NQO2 With UDP-Glucuronosyltransferases Reduces Menadione Toxicity in Neuroblastoma Cells

In Vitro and In Silico Antimalarial Evaluation of FM-AZ, a New Artemisinin Derivative

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