title: Anticancer drugs induce necrosis of human endothelial cells involving both oncosis and apoptosis.
abstract: The endothelium is the first physiological barrier between blood and tissues and can be injured by physical or chemical stress, particularly by the drugs used in cancer therapy. We found that four anticancer agents: etoposide, doxorubicin, bleomycin and paclitaxel induced apoptosis in human umbilical vein endothelial cells (HUVECs) (as judged by DNA fragmentation) with a time- and concentration-dependent decrease in bcl-2 protein but without the involvement of p53. As revealed by immunoblotting, bax protein was expressed in HUVECs treated with 1 mg/ml etoposide whereas bcl-2 protein disappeared. Oncosis occurred parallel to apoptosis with the release of lactate dehydrogenase into the supernatant, and, for doxorubicin and etoposide with the inversion of the distribution of angiotensin I-converting enzyme between supernatant and cells. Among the four tested anticancer drugs, only doxorubicin induced an oxidative stress, with significative malondialdehyde production. Thus, human endothelial cells in confluent cultures seem to be in an equilibrium of resistance to apoptosis related to bcl-2 expression; this equilibrium can be disrupted by a chemical stress, such as the antiproliferative drugs known as pro-apoptotic for tumour cells. For doxorubicin and bleomycin, this cellular toxicity can be related to their unwanted effects in human cancer therapy. Low doses of doxorubicin, paclitaxel or etoposide, however, could induce apoptosis of endothelial cells of new vessels surrounding the tumour, thus leading to specific vessel regression with minimal toxic effects for the endothelium of the other vessels. These findings provide evidence of relationships between endothelial toxicity of anticancer drugs and the key role of bcl-2 for resistance of endothelium cells toward apoptosis; moreover lack of p53 and bax in quiescent cells contributes to resistance of endothelial cells to DNA-damaging agents.
authors.affiliation: Laboratoire de Biochimie A, Hĵpital Saint-Antoine, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Mailloux
authors.forename: K
authors.initials: K
authors.lastname: Grenet
authors.forename: A
authors.initials: A
authors.lastname: Bruneel
authors.forename: B
authors.initials: B
authors.lastname: Bénéteau-Burnat
authors.forename: M
authors.initials: M
authors.lastname: Vaubourdolle
authors.forename: B
authors.initials: B
authors.lastname: Baudin
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001761:Bleomycin / Q000494:pharmacology; D002478:Cells, Cultured / Q000187:drug effects / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005047:Etoposide / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D009336:Necrosis; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D017239:Paclitaxel / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism; D014471:Umbilical Veins / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051028:bcl-2-Associated X Protein
chemical_list: D000970:Antineoplastic Agents; C494826:BAX protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D001761:Bleomycin; D008315:Malondialdehyde; D005047:Etoposide; D004317:Doxorubicin; D007770:L-Lactate Dehydrogenase; D007703:Peptidyl-Dipeptidase A; D005978:Glutathione; D017239:Paclitaxel