Sonidegib, a Novel Inhibitor of Suicidal Erythrocyte Death
Background/Aims: The Hedgehog pathway disrupting drug sonidegib is used in the treatment of basal cell carcinoma. Side effects of sonidegib include anemia, which could result either from impaired erythropoiesis or from loss of erythrocytes e.g. due to suicidal erythrocyte death or eryptosis, which i...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Cell Physiol Biochem Press GmbH & Co KG
2018-06-01
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| Series: | Cellular Physiology and Biochemistry |
| Subjects: | |
| Online Access: | https://www.karger.com/Article/FullText/490820 |
| _version_ | 1818035180747620352 |
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| author | Abdulla Al Mamun Bhuyan Itishri Sahu Hang Cao Florian Lang |
| author_facet | Abdulla Al Mamun Bhuyan Itishri Sahu Hang Cao Florian Lang |
| author_sort | Abdulla Al Mamun Bhuyan |
| collection | DOAJ |
| description | Background/Aims: The Hedgehog pathway disrupting drug sonidegib is used in the treatment of basal cell carcinoma. Side effects of sonidegib include anemia, which could result either from impaired erythropoiesis or from loss of erythrocytes e.g. due to suicidal erythrocyte death or eryptosis, which is characterized by cell membrane scrambling with phosphatidylserine translocation to the cell surface and by cell shrinkage. Eryptosis is stimulated by cell stress, including energy depletion, hyperosmotic shock, oxidative stress and excessive increase of cytosolic Ca2+ activity ([Ca2+]i). The present study explored, whether sonidegib exerts an effect on eryptosis. Methods: Human erythrocytes have been treated with energy depletion (glucose withdrawal for 48 hours), hyperosmotic shock (addition of 550 mM sucrose for 6 hours), oxidative stress (addition of 0.3 mM tert-butylhydroperoxide [tBOOH] for 50 min) or Ca2+ ionophore ionomycin (1 µM for 60 min) in absence and presence of sonidegib (2-6 µg/ ml). After treatment flow cytometry was employed to quantify phosphatidylserine exposure at the cell surface from annexin-V-binding, and cell volume from forward scatter. Hemolysis was estimated from the hemoglobin concentration in the supernatant. Results: In the absence of cell stress exposure to sonidegib did not significantly modify annexin-V-binding or forward scatter, but triggered hemolysis. Energy depletion, hyperosmotic shock, oxidative stress and ionomycin, all markedly and significantly increased the percentage of annexin-V-binding erythrocytes, and decreased the forward scatter. Sonidegib significantly blunted the effect of energy depletion, hyperosmotic shock, and oxidative stress, but not of ionomycin on annexin-V-binding. Sonidegib further significantly blunted the effect of energy depletion, but not of hyperosmotic shock, oxidative stress, and ionomycin on forward scatter. Conclusions: Sonidegib is a novel inhibitor of erythrocyte cell membrane scrambling following energy depletion, hyperosmotic shock and oxidative stress. |
| first_indexed | 2024-12-10T06:50:58Z |
| format | Article |
| id | doaj.art-10492b1b96e7491f84d3ed0f02500571 |
| institution | Directory Open Access Journal |
| issn | 1015-8987 1421-9778 |
| language | English |
| last_indexed | 2024-12-10T06:50:58Z |
| publishDate | 2018-06-01 |
| publisher | Cell Physiol Biochem Press GmbH & Co KG |
| record_format | Article |
| series | Cellular Physiology and Biochemistry |
| spelling | doaj.art-10492b1b96e7491f84d3ed0f025005712022-12-22T01:58:33ZengCell Physiol Biochem Press GmbH & Co KGCellular Physiology and Biochemistry1015-89871421-97782018-06-014741352136410.1159/000490820490820Sonidegib, a Novel Inhibitor of Suicidal Erythrocyte DeathAbdulla Al Mamun BhuyanItishri SahuHang CaoFlorian LangBackground/Aims: The Hedgehog pathway disrupting drug sonidegib is used in the treatment of basal cell carcinoma. Side effects of sonidegib include anemia, which could result either from impaired erythropoiesis or from loss of erythrocytes e.g. due to suicidal erythrocyte death or eryptosis, which is characterized by cell membrane scrambling with phosphatidylserine translocation to the cell surface and by cell shrinkage. Eryptosis is stimulated by cell stress, including energy depletion, hyperosmotic shock, oxidative stress and excessive increase of cytosolic Ca2+ activity ([Ca2+]i). The present study explored, whether sonidegib exerts an effect on eryptosis. Methods: Human erythrocytes have been treated with energy depletion (glucose withdrawal for 48 hours), hyperosmotic shock (addition of 550 mM sucrose for 6 hours), oxidative stress (addition of 0.3 mM tert-butylhydroperoxide [tBOOH] for 50 min) or Ca2+ ionophore ionomycin (1 µM for 60 min) in absence and presence of sonidegib (2-6 µg/ ml). After treatment flow cytometry was employed to quantify phosphatidylserine exposure at the cell surface from annexin-V-binding, and cell volume from forward scatter. Hemolysis was estimated from the hemoglobin concentration in the supernatant. Results: In the absence of cell stress exposure to sonidegib did not significantly modify annexin-V-binding or forward scatter, but triggered hemolysis. Energy depletion, hyperosmotic shock, oxidative stress and ionomycin, all markedly and significantly increased the percentage of annexin-V-binding erythrocytes, and decreased the forward scatter. Sonidegib significantly blunted the effect of energy depletion, hyperosmotic shock, and oxidative stress, but not of ionomycin on annexin-V-binding. Sonidegib further significantly blunted the effect of energy depletion, but not of hyperosmotic shock, oxidative stress, and ionomycin on forward scatter. Conclusions: Sonidegib is a novel inhibitor of erythrocyte cell membrane scrambling following energy depletion, hyperosmotic shock and oxidative stress.https://www.karger.com/Article/FullText/490820PhosphatidylserineEryptosisEnergy depletionOxidative stressHyperosmotic shockIonomycinCalcium |
| spellingShingle | Abdulla Al Mamun Bhuyan Itishri Sahu Hang Cao Florian Lang Sonidegib, a Novel Inhibitor of Suicidal Erythrocyte Death Cellular Physiology and Biochemistry Phosphatidylserine Eryptosis Energy depletion Oxidative stress Hyperosmotic shock Ionomycin Calcium |
| title | Sonidegib, a Novel Inhibitor of Suicidal Erythrocyte Death |
| title_full | Sonidegib, a Novel Inhibitor of Suicidal Erythrocyte Death |
| title_fullStr | Sonidegib, a Novel Inhibitor of Suicidal Erythrocyte Death |
| title_full_unstemmed | Sonidegib, a Novel Inhibitor of Suicidal Erythrocyte Death |
| title_short | Sonidegib, a Novel Inhibitor of Suicidal Erythrocyte Death |
| title_sort | sonidegib a novel inhibitor of suicidal erythrocyte death |
| topic | Phosphatidylserine Eryptosis Energy depletion Oxidative stress Hyperosmotic shock Ionomycin Calcium |
| url | https://www.karger.com/Article/FullText/490820 |
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