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2015 ; 7
(5
): 1616-28
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Induction of suicidal erythrocyte death by nelfinavir
#MMPMID26008229
Bissinger R
; Waibel S
; Lang F
Toxins (Basel)
2015[May]; 7
(5
): 1616-28
PMID26008229
show ga
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.
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