Neutrophil Elastase as a Target in Lung Cancer: the State of the Art
Pp. 3-49 (47)
Alain J.P. Alix,
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.
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