Apigenin-induced ABCC1-mediated efflux of glutathione from mature erythrocytes inhibits the proliferation of Plasmodium falciparum

作者：Fallatah Ohud; Georges Elias^*

来源：International Journal of Antimicrobial Agents, 2017, 50(5): 673-677.

DOI：10.1016/j.ijantimicag.2017.08.014

• Malaria
• Apigenin
• ABCC1 (MRP1)
• Reactive oxygen species
• Glutathione
• Eryptosis

Plasmodium falciparum infection of mature erythrocytes leads to heightened oxidative stress that is tolerated in normal erythrocytes but not in erythrocytes from sickle cell, beta-thalassaemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency hosts. In this report, it was of interest to perturb the redox homeostasis of normal erythrocytes through drug-induced active efflux of glutathione via erythrocyte ABCC1, a member of the C-subfamily of the human ATP-binding cassette (ABC) transporters. To achieve this objective, we made use of apigenin (API), shown previously to activate ABCC1 glutathione efflux in mature erythrocytes. Our results show that API increased ABCC1-mediated efflux of calcein-AM from uninfected erythrocytes, which was reversed with MK571, an inhibitor of ABCC1 drug efflux. Similarly, addition of API to uninfected normal erythrocytes led to a dramatic increase in reactive oxygen species coupled with a significant decrease in intracellular glutathione. Moreover, using P. falciparum-infected normal erythrocytes, we demonstrate that increasing concentrations of API inhibited the proliferation of chloroquine-susceptible (3D7) and -resistant (Dd2) parasites in culture with similar 50% inhibitory concentration (IC50) values (36.02 +/- 2.4 mu M and 34.45 +/- 2.4 mu M, respectively). Interestingly, the presence of API (25 mu M) led to a three-fold decrease in the IC50 of artemisinin compared with artemisinin alone (2.8 +/- 0.7 nM vs. 7.09 +/- 1.5 nM, respectively). Taken together, the findings of this study demonstrate the feasibility of our proposed approach for the development of novel antimalarials by modulating host protein functions that leads to heightened oxidative stress in P. falciparum-infected erythrocytes and inhibits parasite proliferation.

• 出版日期2017-11
• 单位McGill