HMG CoA reductase inhibitors for promoting angiogenesis

Details HMG CoA reductase inhibitors for promoting angiogenesis HMG CoA reductase inhibitors for promoting angiogenesis

2000-06-08

2004-02-10

Weber, Jon P. (Department: 1651)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S510000, C435S189000

Reexamination Certificate

active

06689807

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to methods and compositions for the treatment of conditions associated with vascular insufficiency, and to methods and compositions for screening assays to select agents that are useful for this purpose. In particular, the invention relates to HMG CoA reductase inhibitors and their use in promoting angiogenesis in vivo and in activating Akt in vascular endothelial cells in vitro and in vivo.
BACKGROUND OF THE INVENTION
Akt Protein Kinases
Akt (c-Akt) is a proto-oncogene encoding a serine-threonine kinase (Testa, J. R. and Bellacosa, A.,
Leukemia Res
., 1997, 21:1027-1031). It is the cellular homolog of the viral oncoprotein v-Akt, and is related to protein kinase-C (PKC) within the catalytic domain. However, c-Akt differs from the PKC family members by the presence of a pleckstrin homology (PH) domain at its N-terminus that is involved in the regulation of the activity of the enzyme by growth factors and intracellular signaling molecules. Various extracellular stimuli reportedly activate Akt through the phosphoinositide 3-kinase (PI 3-kinase) pathway (Datta, K. et al.,
J. Biol. Chem
., 1996, 271:30835-30839; Franke, T. F., et al.,
Cell
, 1995, 81:727-736; King, W. G. et al.,
Mol. Cell. Biol
., 1997, 17:4406-4418). The lipid products of the PI 3-kinase reaction reportedly may activate Akt either by binding to the Akt pleckstrin homology (PH) domain (Franke, T. F. et al., 1997, Cell, 88:435:437), or by activating a protein kinase that phosphorylates Akt (Kohn, A. D., et al.,
J. Biol. Chem
., 1996, 271:21920-21926; Stokoe et al.,
Science
, 1997, 277:567-570). Activation of Akt reportedly inhibits apoptosis induced by growth factor withdrawal or irradiation in neural cells, fibroblasts, and lymphocytes (Franke, T. F., et al.,
Science
, 1997, 275:665-668; Hemmings,
Science
, 1997, 275:628-630). Recently, it has been reported that Akt phosphorylates the pro-apoptotic protein Bad leading to Bad inactivation and cell survival (Datta, K., et al.,
Cell
, 1997, 91:231-241; Peso, L., et al.,
Science
, 1997, 278:687-689).
Despite the foregoing speculation, the precise mechanism underlying Akt activation in vivo has yet to be elucidated. Accordingly, a need still exists to identify the precise mechanism underlying Akt activation in vivo and to use such knowledge to develop methods and compositions for treating conditions that are amenable to treatment by Akt activation in vivo, as well as to develop screening assays that are useful for identifying agents which activate Akt in vivo and in vitro.
HMG-CoA Reductase Inhibitors
HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase is the enzyme which catalyzes the rate limiting step of cholesterol biosynthesis. HMG-CoA reductase inhibitors, also known as statins, are molecules which inhibit the enzymatic activity of HMG-CoA reductase and have been used to treat patients suffering from hypercholesterolemia. The first such inhibitor (compactin or Mevastatin) was isolated in 1976 (Endo, A. et al.,
F.E. B.S. Lett
., 72: 323-326, 1976) and since then many other natural and chemically modified versions of Mevastatin have been identified and developed for clinical use, including Lovastatin, and Simvastatin.
Recent studies have shown that, in addition to treatment of hyperlipidemia, HMG-CoA reductase inhibitors are useful in the treatment of acne and/or skin aging (see, e.g. Breton, L. et al., U.S. Pat. No. 5,902,805); can increase nitric oxide (NO)-mediated vasodilation and blood vessel relaxation (see e.g., Liao, J. K. et al., WO 99/18952); and can help prevent a second or additional myocardial infarction (see, e.g., Behounek, B. D. et al., U.S. Pat. No. 5,674,893; Olukotun, A. Y. et al., U.S. Pat. No. 5,622,985).
Additonally, several studies have shown that HMG-CoA reductase inhibitors have anti-angiogenic activity. Feleszko, W. et al.,
Int. J. Cancer
, 81: 560-567 (1999) reported that treatment of a mouse model of tumor-cell induced angiogenesis with a combination of TNF-&agr; and lovastatin produced a significant inhibition of tumor-induced blood-vessel formation whereas treatment with either TNF-&agr; or lovastatin alone showed no angiostatic effects. Jones, M. K. et al.,
Am. J. Physiol
., 276: G1345-GI1355 (1999) reported that mevastatin, an inhibitor of Ras activation, completely blocked the induction of VEGF (a potent angiogenic factor) expression in cultured primary endothelial cells. Kong, D. et al.,
Circulation
, 100(18): I-39, Abstract #194 (1999) reported that simvastatin exerted potent anti-angiogenic effects independent of its cholesterol lowering effects.
SUMMARY OF THE INVENTION
To understand the mechanism by which angiogenic agents such as VEGF promote new blood vessel formation (angiogenesis), we have analyzed the signaling pathways downstream from the growth factor. In particular, we have analyzed Akt signaling in endothelial cells. Akt (also known as Protein Kinase-B, PKB) inhibits apoptotic cell-death and, in particular, inhibits apoptotic cell-death of cardiomyocytes, skeletal myocytes and/or vascular endothelial cells. (See, e.g., U.S. Ser. No. 9/922,633, entitled, “Akt Compositions for Enhancing Survival of Cells”, PCT Application No. PCT/US99/22633, published as WO 00/20025). In the course of analyzing Akt signaling events in an animal model of ischemia, we have surprisingly discovered that activation of Akt signaling in endothelial cells is sufficient to promote angiogenesis. We also have discovered that HMG CoA reductase inhibitors such as simvastatin are potent activators of Akt. In view of these discoveries, we believe that simvastatin and other HMG CoA reductase inhibitors can be used to promote angiogenesis in tissues, and that such inhibitors are useful for treating conditions in which new blood vessel growth is desirable to treat the condition. These discoveries were highly unexpected in view of previous research indicating that HMG CoA reductase inhibitors had angiostatic activity.
According to one aspect of the invention, a method for promoting angiogenesis in a tissue of a subject in need of such treatment is provided. The method involves administering to the subject, an HMG CoA reductase inhibitor in an amount effective to promote angiogenesis in the tissue, preferably in situations where the subject is not otherwise in need of administration of an HMG CoA reductase inhibitor. According to this aspect, the subject may or may not be hyperlipidemic and/or hypercholesterolemic. In certain embodiments, the method further includes the step of detecting angiogenesis in the tissue.
Conditions that can be treated in accordance with this method of the invention (administration by any route, preferably oral administration) are conditions characterized by insufficient vascularization (or predisposition thereto) of the affected tissue, i.e., conditions in which neovascularization (rather than increases in nitric oxide (NO)-mediated vasodilation) is needed to achieve sufficient vascularization in the affected tissue, and that are selected from the following group of conditions: (1) diabetic ulcers, (2) gangrene, (3) surgical or other wounds requiring ncovascularization to facilitate healing; (4) Buerger's syndrome; (5) hypertension; (6) ischemic diseases including, for example, cerebrovascular ischemia, renal ischemia, pulmonary ischemia, limb ischemia, ischemic cardiomyopathy, myocardial ischemia, ischemia of tissues such as, for example, muscle, brain, kidney and lung; and other conditions characterized by a reduction in microvasculature. The preferred method of treatment further includes the step of detecting angiogenesis in the affected tissue following treatment. Exemplary tissues in which angiogenesis can be promoted and, optionally, detected in accordance with this method of the invention include: hypertension; ulcers (e.g., diabetic ulcers); surgical wounds; ischemic tissue, i.e., a tissue having a deficiency in blood as the result of an ischemic disease including, for example, muscle, brain, kidney and lung; ischemic diseases including, for examp

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