Cyclosporin A but not estradiol can protect endothelial cells against etoposide-induced apoptosis.
This study was undertaken to examine the possibilities of endothelial protection toward toxicity of anticancer drugs. To test the hypothesis that estradiol (E2) and cyclosporin A (CsA) can interfere within programmed cell death in human umbilical vein endothelial cells (HUVECs), apoptosis was induced by etoposide with and without E2 or CsA. All the concentrations of E2 tested (from 10(-9) to 10(-5) M) failed to protect HUVECs. For CsA a dual effect was observed: used at 1 or 10 microg/mL in coincubation with etoposide, CsA significantly reduced etoposide-induced apoptosis but complete inhibition was not reached, whereas used at 50 microg/mL CsA did not protect HUVECs anymore and even had deleterious effects. Furthermore, a 24-h pretreatment of HUVECs by CsA at 10 microg/mL significantly protected the cells by preventing both bcl-2 level decrease and caspase-3 activation related to etoposide-induced apoptosis. Protective effects of CsA toward endothelial cells were concentration dependent; in pretreatment at 10 microg/mL, CsA was an effective protector and might contribute in vivo to inhibit obvious toxic effects caused by anticancer drugs.
Mailloux
Agnès
A
Service de Biochimie A, Hôpital Saint-Antoine, AP-HP, Paris, France. agnes.mailloux@sat.ap-hop-paris.fr
Bruneel
Arnaud
A
Vaubourdolle
Michel
M
Baudin
Bruno
B
D000972:Antineoplastic Agents, Phytogenic / Q000037:antagonists & inhibitors / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology*; D019610:Cytoprotection / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004347:Drug Interactions / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D005047:Etoposide / Q000037:antagonists & inhibitors* / Q000633:toxicity; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D019253:Proto-Oncogene Proteins c-bcl-2; D004958:Estradiol; D005047:Etoposide; D016572:Cyclosporine; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases