Matrix proteinase inhibition by AE-941, a multifunctional antiangiogenic compound.
BACKGROUND
Matrix metalloproteinases (MMPs) play an important role in tissue remodeling under normal physiological and pathological conditions and are thus attractive targets for both diagnostic and therapeutic purposes. Here, we examined the effect of AE-941, an orally bioavailable standardized extract made of cartilage that shows significant antiangiogenic and antimetastatic properties in vivo, on the activity of various members of the MMP family.


METHODS
The effect of AE-941 on the activity of MMPs was assessed by fluorimetric assays and by substrate gel zymography.


RESULTS
AE-941 markedly inhibits the gelatinolytic activity of MMP-2 and to a lesser extent those of MMP-1, MMP-7, MMP-9 and MMP-13. AE-941 also inhibited the elastinolytic activities of MMP-2 and MMP-9 as well as MMP-12 (metalloelastase), porcine pancreatic elastase (PPE), and human leukocyte elastase (HLE). Western blot analysis revealed the presence within AE-941 of immunoreactive TIMP-like proteins, suggesting that these proteins may be at least partly responsible for the observed MMP inhibition.


CONCLUSIONS
Taken together, these results demonstrate that AE-941 contains TIMP-like proteins that could be responsible for the specific inhibition of MMPs. Given the recent studies suggesting the presence within this compound of specific inhibitor(s) of endothelial cell proliferation, AE-941 appears as a pleotropic agent able to interfere with several biochemical steps leading to angiogenesis and to other physiopathological conditions. Since AE-941 is currently under Phase III clinical investigations, these findings are also of considerable importance for our understanding of its anticancer properties.
Gingras
D
D
Laboratoire de médecine moléculaire, Hôpital Ste-Justine-UQAM, Centre de cancérologie Charles-Bruneau, Centre de Recherche de l'Hôpital Ste-Justine, 3175, Chemin Côte-Ste-Catherine, Montréal, Québec, Canada H3T 1C5.
Renaud
A
A
Mousseau
N
N
Beaulieu
E
E
Kachra
Z
Z
Béliveau
R
R
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D007700:Kinetics; D061965:Matrix Metalloproteinase Inhibitors; D012697:Serine Endopeptidases / Q000378:metabolism; D014020:Tissue Extracts / Q000737:chemistry / Q000494:pharmacology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000032:analysis
D020533:Angiogenesis Inhibitors; D016326:Extracellular Matrix Proteins; D061965:Matrix Metalloproteinase Inhibitors; D014020:Tissue Extracts; D019714:Tissue Inhibitor of Metalloproteinases; C111481:shark cartilage extract; D012697:Serine Endopeptidases