Abstract
During the Plasmodium erythrocytic cycle, glucose is taken up by glucose transporters (GLUTs) in red blood cells (RBCs) and supplied to parasites via the Plasmodium hexose transporter. Here, we demonstrate that the glucose uptake pathway in infected RBCs (iRBCs) can be hijacked by vitamin C (Vc). GLUTs preferentially transport the oxidized form of Vc, which is subsequently reduced in the cytosol. Vc, which is expected to burden the intracellular reducing capacity, inhibits Plasmodium berghei and Plasmodium falciparum growth. Vc uptake is drastically increased in iRBCs, with a large proportion entering parasites. Increased absorption of Vc causes accumulation of reactive oxygen species, reduced ATP production, and elevated eryptosis in iRBCs and apoptosis in parasites. The level of oxidative stress induced by Vc is significantly higher in iRBCs than uninfected RBCs, not seen in chloroquine or artemisinin-treated iRBCs, and effective in inhibiting chloroquine or artemisinin-resistant parasites. These findings provide important insights into the drug sensitivity of Plasmodium.
Highlights
Usage of vitamin C (Vc) has been suggested in cancer therapy (Cameron and Pauling, 1976, 1978; Chen et al, 2007, 2008)
These results suggest that high doses of daily Vc efficiently prevent Plasmodium berghei infection
The addition of reducing agent glutathione (GSH) prevented absorbance (Figure 2C). These results suggest that Vc uptake by infected RBCs (iRBCs) is predominantly GLUTdependent
Summary
Usage of vitamin C (Vc) has been suggested in cancer therapy (Cameron and Pauling, 1976, 1978; Chen et al, 2007, 2008). GLUTs prefer the oxidized form of Vc, dehydroascorbic acid (DHA), for transportation (Yun et al, 2015). DHA is quickly reduced by nicotinamide adenine dinucleotide phosphate (NADPH) (Linster and Van Schaftingen, 2007). Recent studies have revealed that the selective impact of high-dose Vc on colorectal cancer cells is attributed to the high demand for glucose during the tricarboxylic acid (TCA) cycle and glycolysis transition in these cells (Yun et al, 2015). Glucose transporter 1 (Glut1) is often up-regulated in growing tumor cells (Altenberg and Greulich, 2004). The increase in transported DHA decreases the intracellular reducing power and causes oxidative stress that kills the tumor cells (Yun et al, 2015)
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