title: Stimulating Effect of Manumycin A on Suicidal Erythrocyte Death.
abstract: OBJECTIVE
  The streptomycete derived farnesyltransferase inhibitor Manumycin A triggers apoptosis of tumor cells and is thus considered for the treatment of malignancy. The present study explored whether Manumycin A could similarly stimulate eryptosis, the suicidal death of erythrocytes characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include Ca2+ entry as well as activation of staurosporine sensitive protein kinase C and SB203580 sensitive p38 kinase. The present study explored, whether Manumycin A induces eryptosis and, if so, to shed some light on the mechanisms involved.
  
  
  METHODS
  Phosphatidylserine abundance at the human erythrocyte surface was estimated from annexin-V-binding, cell volume from forward scatter, and hemolysis from hemoglobin concentration in the supernatant.
  
  
  RESULTS
  A 48 hours exposure of human erythrocytes to Manumycin A (≥ 5 µg/ml) significantly increased the percentage of annexin-V-binding cells, significantly decreased forward scatter and significantly incrased hemolysis. The effect of Manumycin A on annexin-V-binding was significantly blunted by removal of extracellular Ca2+, by addition of staurosporine (1 µM) and by addition of SB203580 (2 µM).
  
  
  CONCLUSIONS
  Manumycin A triggers hemolysis, cell shrinkage and phospholipid scrambling of the human erythrocyte cell membrane. The effect on cell membrane scrambling was in part but not fully dependent on entry of extracellular Ca2+, as well as activity of staurosporine and SB203580 sensitive kinases.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Egler
authors.forename: Jens
authors.initials: J
authors.lastname: Zierle
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D048429:Cell Size / Q000187:drug effects; D000072817:Eryptosis / Q000187:drug effects*; D004910:Erythrocyte Membrane / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D026121:Indole Alkaloids / Q000494:pharmacology; D010718:Phosphatidylserines / Q000378:metabolism; D011090:Polyenes / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D017304:Annexin A5; D002227:Carbazoles; D007093:Imidazoles; D026121:Indole Alkaloids; D010718:Phosphatidylserines; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D011725:Pyridines; D017382:Reactive Oxygen Species; C049985:staurosporine aglycone; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; C054474:manumycin; C093642:SB 203580; D002118:Calcium