Neutrophil Elastase as a Target in Lung Cancer
Neutrophil Elastase as a Target in Lung Cancer
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DOI：
10.2174/187152012800617696
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发表时间：
2012-07-01
影响因子：
2.8
通讯作者：
Bourguet, Erika
中科院分区：
文献类型：
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作者：
Moroy, Gautier;Alix, Alain J. P.;Bourguet, Erika
人类中性粒细胞弹性蛋白酶(HNE)是慢性阻塞性肺疾病发生发展的主要因素，最近也参与了非小细胞肺癌的进展。它可以在几个水平上起作用：(I)在细胞内，例如在细胞表面裂解适配分子胰岛素受体底物-1(IRS-1)(Ii)，在细胞外空间内以CD40(III)的形式水解受体，产生弹性蛋白片段，即有效刺激癌细胞侵袭和血管生成的形态弹性因子。这些化合物中的一些可能作为肺癌的治疗剂有价值。然而，现在人们普遍认为肺癌的侵袭和转移涉及蛋白水解级联反应。因此，这里我们将主要关注对HNE和基质金属蛋白酶(MMPs)具有双重抑制能力的天然物质(即脂质及其衍生物、酚类)，特别是基质金属蛋白酶-2。为此，我们最近合成了名为“LipoGalardin”的物质(Moroy G.等人，Biochem。Pharmacol.，2011，81(5)，626-635)表现出这种抑制双功能。最后，我们将提出一个原创性的合成方案来设计一种有效的双头HNE/MMP2抑制剂。
Human neutrophil elastase (HNE), a main actor in the development of chronic obstructive pulmonary diseases, has been recently involved in non-small cell lung cancer progression. It can act at several levels (i) intracellularly, cleaving for instance the adaptor molecule insulin receptor substrate-1 (IRS-1) (ii) at the cell surface, hydrolyzing receptors as CD40 (iii) in the extracellular space, generating elastin fragments i. e. morphoelastokines which potently stimulate cancer cell invasiveness and angiogenesis.Since decades, researchers identified natural compounds and/or synthesized agents which antagonize HNE activity that will be described in this review article. Some of these compounds might be of value as therapeutic agents in lung cancer. However, it is now widely accepted that lung tumor invasion and metastasis involve proteolytic cascades. Accordingly, we will here mainly focus our attention to natural substances able to display a dual inhibitory capacity (i.e. lipids and derivatives, phenolics) towards HNE and matrix metalloproteinases (MMPs), particularly MMP-2. To that purpose, we recently synthesize substances named "LipoGalardin" (Moroy G. et al., Biochem. Pharmacol., 2011, 81(5), 626-635) exhibiting such inhibitory bifunctionality. At last, we will propose an original synthetic scheme for designing a potent biheaded HNE/MMP-2 inhibitor.