Advances in Cancer Drug Targets

Volume: 3

Indexed in: EBSCO, Ulrich's Periodicals Directory

Advances in Cancer Drug Targets is an e-book series that brings together recent expert reviews published on the subject with a focus on strategies for synthesizing and isolating organic compounds and ...
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Neutrophil Elastase as a Target in Lung Cancer: the State of the Art

Pp. 3-49 (47)

Gautier Moroy, Alain J.P. Alix, Janos Sapi, William Hornebeck and Erika Bourguet

Abstract

Human neutrophil elastase (HNE), a main factor 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 had synthesized substances named “LipoGalardin” exhibiting such inhibitory bifunctionality. At last, we will propose an original synthetic scheme for designing a potent biheaded HNE/MMP-2 inhibitor.

Keywords:

Bifunctionality, Caffeic acid phenethyl ester (CAPE), (Dual) inhibitors, Elafin, Elastokines, (-)-Epigallocatechin-3-gallate (EGCG), Flexible docking, Lipogalardin, Lung cancer, Molecular modelling, Neutrophil Elastase, (Potent) angiogenic molecules, Potent biheaded lnhibitor, (Potent) chemiotactic activity.

Affiliation:

Laboratoire de Spectroscopies et Structures Biomoléculaires & Institut de Chimie Moléculaire de Reims, CNRS UMR 7312, Faculté des Sciences Exactes et Naturelles, BP 1039, 51687 Reims Cedex2, France.