Inhibition of lung carcinoma cell growth by high density lipoprotein-associated α-tocopheryl-succinate
Inhibition of lung carcinoma cell growth by high density lipoprotein-associated α-tocopheryl-succinate
复制标题
DOI：
10.1007/s00018-004-4101-4
复制
发表时间：
2004-06-01
影响因子：
8
通讯作者：
Sattler, W
中科院分区：
文献类型：
--
作者：
Hrzenjak, A;Reicher, H;Sattler, W
α-生育酚琥珀酸酯 (alphaTS) 是 α-生育酚的合成抗肿瘤衍生物。在这里，我们研究了游离和高密度脂蛋白亚类 3 (HDL3) 相关 alphaTS 对人类 (A549) 和小鼠 Lewis (LL2) 肺癌细胞生长的影响。游离的和 HDL3 相关的 alphaTS 均以时间和浓度依赖性方式抑制 A549 生长。用富含 alphaTS 的 HDL3 处理 A549 细胞会导致 DNA 片段化和聚（ADP-核糖）聚合酶免疫反应性的时间依赖性下降。摄取实验揭示了选择性 alphaTS 摄取的高能力，超过了全颗粒内吞作用。 A549 细胞中 B 类清道夫受体 I 型 (SR-BI) 的过度表达（介导选择性脂质摄取的主要受体）导致选择性 alphaTS 摄取显着增加，这一发现与细胞完全生长停滞相关。目前的体外研究结果在体内模型中得到了验证：使用野生型、β-半乳糖苷酶或 SR-BI 过表达的 LL2 细胞在 C57BL6 中进行肿瘤接种。肿瘤接种后，动物接受连续六次静脉注射 alphaTS。该实验设置导致接种 SR-BI 过表达 LL2 细胞的动物的肿瘤负荷显着降低，但接种野生型或 β-半乳糖苷酶转染细胞的动物的肿瘤负荷却没有显着降低。基于我们的体外和体内研究结果，我们提出SR-BI可以为HDL3介导的抗肿瘤药物的药物递送提供一种新途径。
alpha-Tocopheryl-succinate (alphaTS) is a synthetic, anti-neoplastic derivative of alpha-tocopherol. Here we studied the effects of free and high-density lipoprotein subclass 3 (HDL3)-associated alphaTS on the growth of human (A549) and mouse Lewis (LL2) lung carcinoma cells. Both free and HDL3-associated alphaTS inhibited A549 growth in a time- and concentration-dependent manner. Treatment of A549 cells with alphaTS-enriched HDL3 led to DNA fragmentation and a time-dependent decrease in immunoreactivity of poly(ADP-ribose)polymerase. Uptake experiments revealed a high capacity for selective alphaTS uptake in excess of holoparticle endocytosis. Overexpression of scavenger receptor class B, type I (SR-BI), the prime receptor mediating selective lipid uptake, in A549 cells resulted in significantly increased selective alphaTS uptake, a finding associated with complete cellular growth arrest. The present in vitro findings were verified in an in vivo model: tumor inoculation in C57BL6 was performed with either wild-type, beta-galactosidase- or SR-BI-overexpressing LL2 cells. After tumor inoculation, the animals received six consecutive intravenous injections of alphaTS. This experimental setup resulted in significantly reduced tumor burden in animals that were inoculated with SR-BI-overexpressing LL2 cells but not in animals inoculated with wild-type or beta-galactocidase-transfected cells. Based on our in vitro and in vivo findings, we propose that SR-BI could provide a novel route for HDL3-mediated drug delivery of anti-neoplastic drugs.