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GSK-3 inhibitors as stimulators of angiogenesis Between 1970 and 1994, cancer claimed the lives of about 123 million Americans. According to the most recent statistics, it is estimated that 1.3 million new cases of cancer will be diagnosed and 555,500 people will die from cancer in the United States in the year 2002. Inhibitors of angiogenesis have received considerable attention because of their anti-cancer opportunities and the market for this therapeutic class is anticipated to reach $1.75 billion by 2006. On the other hand molecules able to stimulate angiogenesis are gaining a place in the treatment of various ischemic diseases. Thrombolytic, antithrombotic and anticoagulant treatments represent the major acute therapeutic options for the treatment of myocardial infarction and peripheral arterial occlusive disease. However, in the days and weeks following myocardial damage, strategies to prevent further ischemic cell death or to promote the recovery of damaged tissue may be of greater advantage, particularly for patients with congestive heart failure. Stimulators of angiogenesis may help meet this clinical demand and in doing so this therapeutic class is expected to boost the market for modulators of angiogenesis by a further $650 million by 2006. The majority of angiogenesis-related molecules in advanced development are VEGF or bFGF homologues. Angiogenesis is a multi-step process. One step involves the escape of endothelial cells from their basement membrane (under the influence of matrix metaloproteinases), and their migration towards target tissues, a process that is mediated by growth factors including VEGF and bFGF. Recently reported data highlight the importance of glycogen synthase kinase-3beta (GSK3beta) in this process. Under normal cell culture conditions, activation of GSK3beta signaling was found to inhibit migration of EC to VEGF or bFGF. Likewise, angiogenesis was inhibited by GSK3beta activation in an in vivo matrigel plug assay, whereas inhibition of GSK3beta signaling enhanced capillary formation. This was not only due to enhanced migration but also due to reduced apoptosis under conditions of cellular stress. LeadDiscovery is about to publish a full analysis describing the therapeutic potential of GSK-3 inhibitors. The present study suggests that stimulation of angiogenesis in the context of cardiovascular disease should be added to the growing list of indications for this therapeutic class. This study also highlights however the role that GSK-3 inhibitors may play in tumor angiogenesis and caution should thus be exercised during therapeutic use. Entry date October, 2002 Adapted from Kim et al, J Biol Chem 2002 Aug 7
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