Anticancer drugs induce necrosis of human endothelial cells involving bothoncosis and apoptosis

The endothelium is the first physiological barrier between blood and tissue s and can be injured by physical or chemical stress, particularly by the dr ugs used in cancer therapy. We found that four anticancer agents: etoposide , doxorubicin, bleomycin and paclitaxel induced apoptosis in human umbilica l vein endothelial cells (HUVECs) (as judged by DNA fragmentation) with a t ime- 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 dehydr ogenase into the supernatant, and, for doxorubicin and etoposide with the i nversion of the distribution of angiotensin I-converting enzyme between sup ernatant and cells. Among the four tested anticancer drugs, only doxorubici n induced an oxidative stress, with significative malondialdehyde productio n. Thus, human endothelial cells in confluent cultures seem to be in an equ ilibrium of resistance to apoptosis related to bcl-2 expression; this equil ibrium can be disrupted by a chemical stress, such as the antiproliferative drags known as pro-apoptotic for tumour cells. For doxorubicin and bleomyc in, this cellular toxicity can be related to their unwanted effects in huma n cancer therapy. Low doses of doxorubicin, paclitaxel or etoposide, howeve r, could induce apoptosis of endothelial cells of new vessels surrounding t he tumour, thus leading to specific vessel regression with minimal toxic ef fects for the endothelium of the other vessels. These findings provide evid ence 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.