Advances in Cancer Drug Targets

Volume: 3

Neutrophil Elastase as a Target in Lung Cancer: the State of the Art

Author(s): Gautier Moroy, Alain J.P. Alix, Janos Sapi, William Hornebeck and Erika Bourguet

Pp: 3-49 (47)

Doi: 10.2174/9781681082332116030003

* (Excluding Mailing and Handling)

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.

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