Effect of miltefosine on erythrocytes

- In erythrocytes the antimicrobial drug miltefosine increases cytosolic Ca2+ activity.
- Miltefosine treatment is followed by cell shrinkage.
- Miltefosine treatment induces cell membrane scrambling.
- The effect of miltefosine is blunted in the absence of extracellular Ca2+.
- Miltefosine thus triggers Ca2+ entry leading to eryptosis, the suicidal erythrocyte death.

BackgroundMiltefosine, an alkylphosphocholine drug with antiparasite, antibacterial, antifungal and antineoplastic potency, is the only oral drug that can be used to treat visceral and cutaneous leishmaniasis. The effect of miltefosine is at least partially due to triggering of apoptosis. Similar to apoptosis of nucleated cells, erythrocytes may enter suicidal death or eryptosis, which is characterized by cell shrinkage and by cell membrane scrambling with phosphatidylserine-exposure at the erythrocyte surface. Eryptosis may be triggered following increase of cytosolic Ca2+-level ([Ca2+]i). The present study explored, whether miltefosine elicits eryptosis.MethodsCell volume has been estimated from forward scatter, phosphatidylserine-exposure from annexin-V-binding, hemolysis from hemoglobin release, [Ca2+]i from Fluo3-fluorescence.ResultsA 48 h exposure to miltefosine (⩾4.9 μM) was followed by significant decrease of forward scatter and significant increase of annexin-V-binding. The effect was paralleled by significant increase of [Ca2+]i. The annexin-V-binding following miltefosine treatment was significantly blunted in the nominal absence of extracellular Ca2+.ConclusionMiltefosine stimulates eryptosis, an effect at least partially due to stimulation of Ca2+ entry.