Vicrostatin - an anti-invasive multi-integrin targeting chimeric disintegrin with tumor anti-angiogenic and pro-apoptotic activities.
Vicrostatin - an anti-invasive multi-integrin targeting chimeric disintegrin with tumor anti-angiogenic and pro-apoptotic activities.
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DOI：
10.1371/journal.pone.0010929
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发表时间：
2010-06-03
期刊：
影响因子：
3.7
通讯作者：
Markland FS Jr
中科院分区：
文献类型：
--
作者：
Minea RO;Helchowski CM;Zidovetzki SJ;Costa FK;Swenson SD;Markland FS Jr
与其他整合素靶向策略类似，去整合素先前已在动物癌症模型中显示出良好的疗效，具有有利的药理学属性和翻译潜力。然而，众所周知，这些多肽难以重组产生，因为它们的特定结构需要多个二硫键的正确配对以获得生物活性。在这里，我们表明，序列工程解整合素（称为vicrostatin或VCN）可以可靠地直接在折纸B E的氧化细胞质中大规模生产。杆菌通过多个整联蛋白连接（即，αvβ3、αvβ5和α5β1），VCN靶向内皮细胞和癌细胞，显著抑制它们通过重建基底膜的运动性。有趣的是，以不同于其他整联蛋白配体的方式，但让人想起一些ECM衍生的内源性抗血管生成片段先前在文献中描述的，VCN深刻地破坏内皮细胞（EC）的肌动蛋白细胞骨架诱导应力纤维和肌动蛋白重组的快速解体，最终干扰EC的侵入和形成管（tubulogenesis）的能力。此外，在这里，我们第一次表明，除了去整合素的tubulogenic EC夹在体外两个基质胶层之间的负面影响他们的生存，尽管存在丰富的haptotactic线索。在具有不同生长特征的两种动物癌症模型中进一步体内评估VCN（LVCN）的脂质体制剂。我们的数据表明，LVCN是耐受性良好，同时发挥显着延迟肿瘤生长和增加治疗动物的生存。这些结果可以部分解释由LVCN诱导的有效的肿瘤抗血管生成和促凋亡作用。
Similar to other integrin-targeting strategies, disintegrins have previously shown good efficacy in animal cancer models with favorable pharmacological attributes and translational potential. Nonetheless, these polypeptides are notoriously difficult to produce recombinantly due to their particular structure requiring the correct pairing of multiple disulfide bonds for biological activity. Here, we show that a sequence-engineered disintegrin (called vicrostatin or VCN) can be reliably produced in large scale amounts directly in the oxidative cytoplasm of Origami B E. coli. Through multiple integrin ligation (i.e., αvβ3, αvβ5, and α5β1), VCN targets both endothelial and cancer cells significantly inhibiting their motility through a reconstituted basement membrane. Interestingly, in a manner distinct from other integrin ligands but reminiscent of some ECM-derived endogenous anti-angiogenic fragments previously described in the literature, VCN profoundly disrupts the actin cytoskeleton of endothelial cells (EC) inducing a rapid disassembly of stress fibers and actin reorganization, ultimately interfering with EC's ability to invade and form tubes (tubulogenesis). Moreover, here we show for the first time that the addition of a disintegrin to tubulogenic EC sandwiched in vitro between two Matrigel layers negatively impacts their survival despite the presence of abundant haptotactic cues. A liposomal formulation of VCN (LVCN) was further evaluated in vivo in two animal cancer models with different growth characteristics. Our data demonstrate that LVCN is well tolerated while exerting a significant delay in tumor growth and an increase in the survival of treated animals. These results can be partially explained by potent tumor anti-angiogenic and pro-apoptotic effects induced by LVCN.
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影响因子：
11.2
作者：
Barkan D;Kleinman H;Simmons JL;Asmussen H;Kamaraju AK;Hoenorhoff MJ;Liu ZY;Costes SV;Cho EH;Lockett S;Khanna C;Chambers AF;Green JE
通讯作者：
Green JE
影响因子：
9.8
作者：
Golubkov, Vladislav;Hawes, Debra;Markland, Francis S.
通讯作者：
Markland, Francis S.
DOI：
10.1073/pnas.0404201101
发表时间：
2004-09-07
影响因子：
11.1
作者：
Artoni, A;Li, JH;Coller, BS
通讯作者：
Coller, BS
影响因子：
15.9
作者：
BROOKS, PC;STROMBLAD, S;CHERESH, DA
通讯作者：
CHERESH, DA
影响因子：
14.5
作者：
Contois L;Akalu A;Brooks PC
通讯作者：
Brooks PC