Stimulation of erythrocyte phosphatidylserine exposure by paclitaxel.
Side effects of cytostatic treatment include development of anemia resulting from either decreased generation or accelerated clearance of circulating erythrocytes. Recent experiments revealed a novel kind of stress-induced erythrocyte death, i.e. eryptosis, which is characterized by enhanced cytosolic Ca(2+) levels, increased ceramide formation and exposure of phosphatidylserine at the cell surface. The present study explored whether cytostatic treatment with paclitaxel (Taxol) triggers eryptosis. Blood was drawn from cancer patients before and after infusion of 175 mg/m2 Taxol. The treatment significantly decreased the hematocrit and significantly increased the percentage of annexin-V-binding erythrocytes in vivo (by 37%). In vitro incubation of human erythrocytes with 10 microM paclitaxel again significantly increased annexin-V-binding (by 129%) and augmented the increase of annexin-V-binding following cellular stress. The enhanced phosphatidylserine exposure was not dependent on caspase-activity but paralleled by erythrocyte shrinkage, increase of cytosolic Ca(2+) activity, ceramide formation and activation of calpain. Phosphatidylserine exposure was similarly induced by docetaxel but not by carboplatin or doxorubicin. Moreover, eryptosis was triggered by the Ca(2+) ionophore ionomycin (10 microM). In mice, ionomycin-treated eryptotic erythrocytes were rapidly cleared from circulating blood and sequestrated into the spleen. In conclusion, our data strongly suggest that paclitaxel-induced anemia is at least partially due to induction of eryptosis.
Lang
Philipp A
PA
Department of Physiology and Department of Obstetrics and Gynaecology, University of Tübingen.
Huober
Jens
J
Bachmann
Cornelia
C
Kempe
Daniela S
DS
Sobiesiak
Malgorzata
M
Akel
Ahmad
A
Niemoeller
Olivier M
OM
Dreischer
Peter
P
Eisele
Kerstin
K
Klarl
Barbara A
BA
Gulbins
Erich
E
Lang
Florian
F
Wieder
Thomas
T
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001772:Blood Cell Count; D002118:Calcium / Q000378:metabolism; D016190:Carboplatin / Q000008:administration & dosage; D048429:Cell Size / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D016889:Endometrial Neoplasms / Q000097:blood / Q000188:drug therapy; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006400:Hematocrit; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009997:Osmotic Pressure; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D010718:Phosphatidylserines / Q000097:blood / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013997:Time Factors; D000093542:Gemcitabine
D002518:Ceramides; D010718:Phosphatidylserines; D003841:Deoxycytidine; D016190:Carboplatin; D013108:Sphingomyelin Phosphodiesterase; D017239:Paclitaxel; D002118:Calcium; D000093542:Gemcitabine