Pro-apoptotic effects of antimalarial drugs do not affect mature human erythrocytes

Totino, Paulo Renato Rivas; Daniel-Ribeiro, Cláudio Tadeu; Ferreira-da-Cruz, Maria de Fátima

doi:10.1016/j.actatropica.2009.08.002

Cited by 10 publications

(6 citation statements)

References 30 publications

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“…The mefloquine concentration required for stimulation of erythrocyte cell membrane scrambling is similar (forward scatter) or slightly higher (annexin-V-binding) than the plasma concentrations (2.5 µg/ml) reported in vivo [66]. The observations are at variance to an earlier paper failing to observe an effect of mefloquine on phosphatidylserine abundance at the erythrocyte surface [67]. …”

Section: Discussioncontrasting

confidence: 56%

Stimulation of Suicidal Erythrocyte Death by the Antimalarial Drug Mefloquine

Bissinger

Barking

Alzoubi

et al. 2015

Cell Physiol Biochem

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Background: The antimalarial drug mefloquine has previously been shown to stimulate apoptosis of nucleated cells. Similar to apoptosis, erythrocytes may enter suicidal death or eryptosis, which is characterized by cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane with phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include oxidative stress, increase of cytosolic Ca²⁺-activity ([Ca²⁺]_i), and ceramide. Methods: 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, [Ca²⁺]_i from Fluo3-fluorescence, and ceramide abundance from specific antibody binding. Results: A 48 h treatment of human erythrocytes with mefloquine significantly increased the percentage of annexin-V-binding cells (≥5 µg/ml), significantly decreased forward scatter (≥5 µg/ml), significantly increased ROS abundance (5 µg/ml), significantly increased [Ca²⁺]_i (7.5 µg/ml) and significantly increased ceramide abundance (10 µg/ml). The up-regulation of annexin-V-binding following mefloquine treatment was significantly blunted but not abolished by removal of extracellular Ca²⁺. Even in the absence of extracellular Ca²⁺, mefloquine significantly increased annexin-V-binding. Conclusions: Mefloquine treatment leads to erythrocyte shrinkage and erythrocyte membrane scrambling, effects at least partially due to induction of oxidative stress, increase of [Ca²⁺]_i and up-regulation of ceramide abundance.

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Section: Discussioncontrasting

confidence: 56%

Stimulation of Suicidal Erythrocyte Death by the Antimalarial Drug Mefloquine

Bissinger

Barking

Alzoubi

et al. 2015

Cell Physiol Biochem

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“…Our studies have shown that induction of apoptosis is not limited to parasitized RBCs (pRBCs) but also occurs in non-parasitized RBCs (nRBCs), pointing to an involvement of both pRBC and nRBC in the pathogenesis of malaria through deflagration of suicide processes (Totino et al, 2009, 2011, 2013, 2014). Thus, the present review covers evidence implicating erythrocytic apoptosis in the pathogenesis of severe anemia, a common complication of malaria that represents an important public health concern strongly related to mortality in children and pregnant women living in malaria-hyperendemic regions of sub-Saharan Africa (Schantz-Dunn and Nour, 2009; Muoneke et al, 2012).…”

Section: Introductionmentioning

confidence: 75%

Evidencing the Role of Erythrocytic Apoptosis in Malarial Anemia

Totino

Daniel-Ribeiro

Ferreira-da-Cruz

2016

Front. Cell. Infect. Microbiol.

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In the last decade it has become clear that, similarly to nucleated cells, enucleated red blood cells (RBCs) are susceptible to programmed apoptotic cell death. Erythrocytic apoptosis seems to play a role in physiological clearance of aged RBCs, but it may also be implicated in anemia of different etiological sources including drug therapy and infectious diseases. In malaria, severe anemia is a common complication leading to death of children and pregnant women living in malaria-endemic regions of Africa. The pathogenesis of malarial anemia is multifactorial and involves both ineffective production of RBCs by the bone marrow and premature elimination of non-parasitized RBCs, phenomena potentially associated with apoptosis. In the present overview, we discuss evidences associating erythrocytic apoptosis with the pathogenesis of severe malarial anemia, as well as with regulation of parasite clearance in malaria. Efforts to understand the role of erythrocytic apoptosis in malarial anemia can help to identify potential targets for therapeutic intervention based on apoptotic pathways and consequently, mitigate the harmful impact of malaria in global public health.

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“…It has been discovered that inhibition of B cell lymphoma 2 (Bcl2), a critical anti-apoptotic protein in hepatocytes, decreased liver stage parasites in infected Hepa 1–6 cell cultures [35] . At the same time, antimalarial drugs cannot be excluded from malarial anemia because they induce apoptosis in nucleated cells [36] .…”

Section: Discussionmentioning

confidence: 99%