Anticancer drugs induce necrosis of human endothelial cells involving both oncosis and apoptosis
Anticancer drugs induce necrosis of human endothelial cells involving both oncosis and apoptosis
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DOI：
10.1078/0171-9335-00171
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发表时间：
2001-06-01
影响因子：
6.6
通讯作者：
Baudin, B
中科院分区：
文献类型：
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作者：
Mailloux, A;Grenet, K;Baudin, B
内皮是血液和组织之间的第一道生理屏障，可能会因物理或化学应激而受损，尤其是癌症治疗中使用的药物。我们发现四种抗癌药物：依托泊苷、阿霉素、博莱霉素和紫杉醇可诱导人脐静脉内皮细胞 (HUVEC) 凋亡（通过 DNA 片段化判断），bcl-2 蛋白呈时间和浓度依赖性下降，但 p53 不参与其中。免疫印迹显示，在用 1 mg/ml 依托泊苷处理的 HUVEC 中，bax 蛋白表达，而 bcl-2 蛋白消失。随着乳酸脱氢酶释放到上清液中，肿瘤形成与细胞凋亡同时发生，并且对于阿霉素和依托泊苷来说，随着血管紧张素I转换酶在上清液和细胞之间的分布反转。在四种测试的抗癌药物中，只有阿霉素会诱导氧化应激，并产生大量丙二醛。因此，汇合培养物中的人内皮细胞似乎处于与 bcl-2 表达相关的细胞凋亡抵抗平衡；这种平衡可能会被化学应激破坏，例如被称为肿瘤细胞促凋亡的抗增殖药物。对于阿霉素和博莱霉素，这种细胞毒性可能与其在人类癌症治疗中的不良影响有关。然而，低剂量的阿霉素、紫杉醇或依托泊苷可以诱导肿瘤周围新血管的内皮细胞凋亡，从而导致特定血管消退，而对其他血管内皮的毒性作用最小。这些发现提供了抗癌药物的内皮毒性与 bcl-2 在内皮细胞抵抗细胞凋亡中的关键作用之间关系的证据。此外，静止细胞中p53和bax的缺乏有助于内皮细胞对DNA损伤剂的抵抗。
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 drags 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.