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.

Design of ultrasensitive probes for human neutrophil elastase through hybrid combinatorial substrate library profiling

“…NE is released by neutrophils during inflammation, and its function is generally thought to be to degrade host tissue and destroy bacteria. Extended tissue destruction is deleterious, and NE is also involved in the development of chronic obstructive pulmonary diseases and in nonsmall-cell lung cancer progression (15). NE belongs to one of the most investigated protease families and has very broad substrate specificity (16).…”

Three-dimensional Structure of a Kunitz-type Inhibitor in Complex with an Elastase-like Enzyme

“…Elastin is particularly abundant in the lungs but is also present in arteries, skin, and ligaments. Consequently, abnormal elastolytic activities are considered to play important roles in tissue destruction associated with several diseases (2)(3)(4)(5)(7)(8)(9)(10). Under normal physiological conditions, human neuthrophil elastase (HNE) 2 is tightly controlled by its endogenous inhibitors.…”

Rational Design of Antibody Protease Inhibitors

“…Currently, an endogenous protein HNE inhibitor, Elafin, is in clinic trials for its effect on the postoperative inflammatory reactions in esophageal cancer surgery, coronary artery bypass surgery, and kidney transplantation, as well as pre-clinical development for several inflammatory conditions/diseases. 26 Elafin has high in vitro potency against HNE (K i = 0.6 nM) 27 but suffers from a short half-life that could limit its therapeutic utility. Rationally designed antibody protease inhibitors with comparable potency and superior pharmacokinetic properties may represent a promising alternative.…”