OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesis
OTX008, a selective small-molecule inhibitor of galectin-1, downregulates cancer cell proliferation, invasion and tumour angiogenesis
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DOI：
10.1016/j.ejca.2014.06.015
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发表时间：
2014-09-01
影响因子：
8.4
通讯作者：
Raymond, Eric
中科院分区：
文献类型：
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作者：
Astorgues-Xerri, Lucile;Riveiro, Maria E.;Raymond, Eric
背景：半乳糖凝集素1（Galectin-1，Gal 1）是一种碳水化合物结合蛋白，与癌细胞增殖、侵袭和肿瘤血管生成有关。最近出现了几种Gal 1靶向化合物。OTX 008是设计用于结合Gal 1两亲性β-折叠构象的杯芳烃衍生物。我们的研究有助于目前的理解Gal 1在癌症进展中的作用，提供一种新的小分子Gal 1-inhibitors.Methods的抗肿瘤活性的机制的见解：我们在体外评估了一组人癌细胞系中的OTX 008效应。对于体内研究，采用卵巢异种移植模型来分析抗肿瘤活性。结果：在体外培养的癌细胞中，OTX 008在微摩尔浓度下可抑制肿瘤细胞的增殖和侵袭。抗增殖作用与Gal 1在一大组细胞系中的表达相关。此外，表达上皮分化标志物的细胞系比间充质细胞对OTX 008更敏感。在SQ 20 B和A2780- 1A 9细胞中，OTX 008抑制Gal 1表达和ERK 1/2和AKT依赖性存活途径，并通过CDK 1诱导G2/M细胞周期阻滞。OTX 008增强了Semaphorin-3A（Sema 3A）在SQ 20 B细胞中的抗增殖作用，并逆转了外源性Gal 1诱导的侵袭。在体内，OTX 008抑制A2780- 1A 9异种移植物的生长。OTX 008治疗与治疗的肿瘤中Gal 1和Ki 67的下调以及微血管密度和VEGFR 2表达的降低相关。最后，联合研究表明，OTX 008协同作用与几种细胞毒性和靶向治疗，主要是当OTX 008是administered first.Conclusion：这项研究提供了深入了解Gal 1在癌症进展中的作用，以及OTX 008的作用机制，并支持其作为一种抗癌剂的进一步发展。(C)2014爱思唯尔有限公司版权所有。
Background: Galectin-1 (Gal1), a carbohydrate-binding protein is implicated in cancer cell proliferation, invasion and tumour angiogenesis. Several Gal1-targeting compounds have recently emerged. OTX008 is a calixarene derivative designed to bind the Gal1 amphipathic beta-sheet conformation. Our study contributes to the current understanding of the role of Gal1 in cancer progression, providing mechanistic insights into the anti-tumoural activity of a novel small molecule Gal1-inhibitor.Methods: We evaluated in vitro OTX008 effects in a panel of human cancer cell lines. For in vivo studies, an ovarian xenograft model was employed to analyse the antitumour activity. Finally, combination studies were performed to analyse potential synergistic effects of OTX008.Results: In cultured cancer cells, OTX008 inhibited proliferation and invasion at micromolar concentrations. Antiproliferative effects correlated with Gal1 expression across a large panel of cell lines. Furthermore, cell lines expressing epithelial differentiation markers were more sensitive than mesenchymal cells to OTX008. In SQ20B and A2780-1A9 cells, OTX008 inhibited Gal1 expression and ERK1/2 and AKT-dependent survival pathways, and induced G2/M cell cycle arrest through CDK1. OTX008 enhanced the antiproliferative effects of Semaphorin-3A (Sema3A) in SQ20B cells and reversed invasion induced by exogenous Gal1. In vivo, OTX008 inhibited growth of A2780-1A9 xenografts. OTX008 treatment was associated with downregulation of Gal1 and Ki67 in treated tumours, as well as decreased microvessel density and VEGFR2 expression. Finally, combination studies showed OTX008 synergy with several cytotoxic and targeted therapies, principally when OTX008 was administered first.Conclusion: This study provides insights into the role of Gal1 in cancer progression as well as OTX008 mechanism of action, and supports its further development as an anticancer agent. (C) 2014 Elsevier Ltd. All rights reserved.