Matrix proteinase inhibition by AE-941, a multifunctional antiangiogenic compound

Background: Matrix metalloproteinases (MMPs) play an important role in tiss ue remodelling under normal physiological and pathological conditions and a re thus attractive targets for both diagnostic and therapeutic purposes. He re, we examined the effect of AE -941, an orally bioavailable standardized extract made of cartilage that shows significant antiangiogenic and antimet astatic properties in vivo, on the activity of various members of the MMP f amily. Materials and Methods: The effect of AE -941 on the activity of MMPs was assessed by fluorimetric assays and by substrate gel zymography. Resul ts: 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 inhibit ed the elastinolytic activities of MMP-2 and MMP-9 as well as MMP-12 (metal loelastase), porcine pancreatic elastase (PPE), and human leukocyte elastas e (HLE). Western blot analysis revealed the presence within AE -941 of immu noreactive TIMP-like proteins, suggesting that these proteins may be at lea st partly responsible for the observed MMP inhibition. Conclusions: Taken t ogether, 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 sp ecific inhibitor(s) of endothelial cell proliferation, AE -941 appears as a pleotropic agent able to interfere with several biochemical steps leasing to angiogenesis and to other physiopathological conditions. Since AE -941 i s currently under Phase III clinical investigations, these findings are als o of considerable importance for our understanding of its anticancer proper ties.