Abstract
The HIV protease inhibitor, nelfinavir, primarily used for the treatment of HIV infections, has later been shown to be effective in various infectious diseases including malaria. Nelfinavir may trigger mitochondria-independent cell death. Erythrocytes may undergo eryptosis, a mitochondria-independent suicidal cell death characterized by cell shrinkage and phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include oxidative stress and increase of cytosolic Ca2+-activity ([Ca2+]i). During malaria, accelerated death of infected erythrocytes may decrease parasitemia and thus favorably influence the clinical course of the disease. In the present study, phosphatidylserine abundance at the cell surface was estimated from annexin V binding, cell volume from forward scatter, reactive oxidant species (ROS) from 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence, and [Ca2+]i from Fluo3-fluorescence. A 48 h treatment of human erythrocytes with nelfinavir significantly increased the percentage of annexin-V-binding cells (≥5µg/mL), significantly decreased forward scatter (≥2.5µg/mL), significantly increased ROS abundance (10 µg/mL), and significantly increased [Ca2+]i (≥5 µg/mL). The up-regulation of annexin-V-binding following nelfinavir treatment was significantly blunted, but not abolished by either addition of the antioxidant N-acetylcysteine (1 mM) or removal of extracellular Ca2+. In conclusion, exposure of erythrocytes to nelfinavir induces oxidative stress and Ca2+ entry, thus leading to suicidal erythrocyte death characterized by erythrocyte shrinkage and erythrocyte membrane scrambling.
Highlights
Nelfinavir, a specific HIV protease inhibitor, has originally been developed for the treatment of HIV infections and subsequently been shown to be effective in further infectious diseases including SARS, tuberculosis, and malaria [1,2,3,4,5]
In analogy to apoptosis of nucleated cells, erythrocytes could enter eryptosis, a suicidal death characterized by cell shrinkage [8] and translocation of phosphatidylserine from the cell interior to the erythrocyte surface [9]
The present study explored whether nelfinavir is capable to trigger eryptosis, the suicidal erythrocyte death
Summary
Nelfinavir, a specific HIV protease inhibitor, has originally been developed for the treatment of HIV infections and subsequently been shown to be effective in further infectious diseases including SARS, tuberculosis, and malaria [1,2,3,4,5]. Nelfinavir may trigger death of tumor cells and counteracts malignancy [2,3,6,7]. In analogy to apoptosis of nucleated cells, erythrocytes could enter eryptosis, a suicidal death characterized by cell shrinkage [8] and translocation of phosphatidylserine from the cell interior to the erythrocyte surface [9]. Eryptosis may be stimulated by casein kinase 1α, Janus-activated kinase. The present study explored, whether and how nelfinavir stimulates eryptosis. To this end, erythrocytes from healthy volunteers were exposed to nelfinavir and phosphatidylserine abundance at the erythrocyte surface, cell volume, abundance of reactive oxidant species and [Ca2+]i determined utilizing flow cytometry
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