title: Neutrophil elastase as a target in lung cancer.
abstract: 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.
authors.affiliation: Université de Reims Champagne- Ardenne, Faculté des Sciences, IFR53 Biomolécules, Laboratoire de Spectroscopies et Structures Biomoléculaires (LSSBM, EA 4303) BP 1039, 51687 Reims Cedex2, France.
authors.forename: Gautier
authors.initials: G
authors.lastname: Moroy
authors.forename: Alain J P
authors.initials: AJ
authors.lastname: Alix
authors.forename: Janos
authors.initials: J
authors.lastname: Sapi
authors.forename: William
authors.initials: W
authors.lastname: Hornebeck
authors.forename: Erika
authors.initials: E
authors.lastname: Bourguet
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D019013:CD40 Antigens / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004549:Elastin / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000627:therapeutic use*; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008958:Models, Molecular; D000515:alpha 1-Antitrypsin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019013:CD40 Antigens; D004791:Enzyme Inhibitors; D055504:Insulin Receptor Substrate Proteins; D061965:Matrix Metalloproteinase Inhibitors; D000515:alpha 1-Antitrypsin; D004549:Elastin; D019272:Leukocyte Elastase; D020782:Matrix Metalloproteinases