Abstract
Shikonin, the most important component of Lithospermum erythrorhizon, has previously been shown to exert antioxidant, anti-inflammatory, antithrombotic, antiviral, antimicrobial and anticancer effects. The anticancer effect has been attributed to the stimulation of suicidal cell death or apoptosis. Similar to the apoptosis of nucleated cells, erythrocytes may experience eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and by phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include the increase of cytosolic Ca2+-activity ([Ca2+]i) and ceramide formation. The present study explored whether Shikonin stimulates eryptosis. To this end, Fluo 3 fluorescence was measured to quantify [Ca2+]i, forward scatter to estimate cell volume, annexin V binding to identify phosphatidylserine-exposing erythrocytes, hemoglobin release to determine hemolysis and antibodies to quantify ceramide abundance. As a result, a 48 h exposure of human erythrocytes to Shikonin (1 µM) significantly increased [Ca2+]i, increased ceramide abundance, decreased forward scatter and increased annexin V binding. The effect of Shikonin (1 µM) on annexin V binding was significantly blunted, but not abolished by the removal of extracellular Ca2+. In conclusion, Shikonin stimulates suicidal erythrocyte death or eryptosis, an effect at least partially due to the stimulation of Ca2+ entry and ceramide formation.
Highlights
Shikonin, a naphthoquinone, is the most important component of Lithospermum erythrorhizon, a traditional Chinese herbal medicine [1]
The present study explored whether the naphthoquinone Shikonin triggers eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and phosphatidylserine translocation
As both hallmarks of eryptosis are stimulated by the increase of cytosolic Ca2+ activity ([Ca2+]i), the effect of Shikonin on [Ca2+]i was tested in a first series of experiments
Summary
A naphthoquinone, is the most important component of Lithospermum erythrorhizon, a traditional Chinese herbal medicine [1]. The anticancer effect of Shikonin has been attributed at least in part to the stimulation of suicidal cell death or apoptosis [9,10,11,12,13,14,15,16,17]. Similar to the apoptosis of nucleated cells, erythrocytes may undergo eryptosis, a suicidal erythrocyte death characterized by phosphatidylserine translocation and cell shrinkage [25]. The present study explored, whether and, if so, how Shikonin stimulates eryptosis. [Ca2+]i, cell volume and phosphatidylserine exposure were determined in the absence and presence of Shikonin
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