Department of Biology, Xavier University of Louisiana, New Orleans, Louisiana, United States of America.
PLoS One. 2011 Jan 6;6(1):e15905. doi: 10.1371/journal.pone.0015905.
Angiogenesis is a hallmark of tumor development and metastasis and now a validated target for cancer treatment. We previously reported that a novel dimer peptide (apoEdp) derived from the receptor binding region of human apolipoprotein E (apoE) inhibits virus-induced angiogenesis. However, its role in tumor anti-angiogenesis is unknown. This study demonstrates that apoEdp has anti-angiogenic property in vivo through reduction of tumor growth in a mouse model and ocular angiogenesis in a rabbit eye model. Our in vitro studies show that apoEdp inhibits human umbilical vein endothelial cell proliferation, migration, invasion and capillary tube formation. We document that apoEdp inhibits vascular endothelial growth factor-induced Flk-1 activation as well as downstream signaling pathways that involve c-Src, Akt, eNOS, FAK, and ERK1/2. These in vitro data suggest potential sites of the apoE dipeptide inhibition that could occur in vivo.This is the first evidence that a synthetic dimer peptide mimicking human apoE has anti-angiogenesis functions and could be an anti-tumor drug candidate.
血管生成是肿瘤发展和转移的一个标志，现在已成为癌症治疗的一个有效靶点。我们之前曾报道，一种新型二聚体肽（apoEdp）来源于人载脂蛋白 E（apoE）的受体结合区，可抑制病毒诱导的血管生成。然而，其在肿瘤抗血管生成中的作用尚不清楚。本研究通过在小鼠模型中减少肿瘤生长和兔眼模型中的眼血管生成，证明了 apoEdp 具有体内抗血管生成的特性。我们的体外研究表明，apoEdp 可抑制人脐静脉内皮细胞的增殖、迁移、侵袭和毛细血管形成。我们记录到 apoEdp 可抑制血管内皮生长因子诱导的 Flk-1 激活以及涉及 c-Src、Akt、eNOS、FAK 和 ERK1/2 的下游信号通路。这些体外数据提示 apoE 二肽抑制的潜在部位可能在体内发生。这是首例证明模拟人载脂蛋白 E 的合成二聚体肽具有抗血管生成功能并可能成为抗肿瘤药物候选物的证据。
