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.