Tamoxifen as a dual chemopreventative and anti-atherosclerosis treatment

According to the American Heart Association cardiovascular diseases have been the most common cause of death in the US each year with the exception of 1918. In 1998, this group of diseases claimed the lives of nearly 1 million Americans, which translates to 40% of all deaths and strikingly more people die from cardiovascular disease than the next six leading causes of death combined. If cardiovascular disease were to be eliminated, the average life expectancy would rise by 7 years.

Atherosclerosis is common to many cardiovascular diseases and is characterized by arterial wall thickening and loss of elasticity and the formation of plaques that can rupture with consequent thrombosis. Atherosclerosis affected nearly 174 million individuals in the major pharmaceutical markets in 2000. During 2000-2010, total sales of anti-atherosclerosis therapies will grow robustly, to in excess of US$13.7billion by 2008.

Atherosclerotic plaques consist of accumulated intracellular and extracellular lipids, smooth muscle cells, connective tissue, and glycosaminoglycans. The earliest detectable lesion of atherosclerosis is the fatty streak consisting of lipid-laden foam cells. These cells are macrophages that have migrated as monocytes from the circulation into the subendothelial layer of the intima. A primary lipid found in foam cells is cholesteryl ester, which is formed from cholesterol and long-chain fatty acyl-coenzyme A in the presence of acyl-CoA:cholesterol acetyltransferase (ACAT).

After anti-platelet therapies, statins, which prevent the synthesis of cholesterol by inhibiting HMG-CoA reductase inhibitors, are the second-most-prescribed class in atherosclerotic patients making. Although there will be an increase in sales of statins, the market value of this class will fall due to generics price erosion and the launch of successful novel therapies. Hence research into novel anti-hypercholesterolemic therapeutics represents an important area of drug discovery. ACAT inhibitors, which act downstream to HMG-CoA reductase inhibitors (statins), represent a novel approach to the inhibition of atherosclerosis.

Although early ACAT inhibitors gave disappointing results in clinical trials due to their very low efficacy and adrenotoxicity, the discovery of two isoforms of the enzyme, namely ACAT1 and ACAT2, with different substrate specificity and different potential function, has allowed improved specificity. Consequently, Pfizer's Avasimibe was in phase III clinical trials as anti-hyperlipidemic and anti-atherosclerotic agent although development has now been discontinued. Eflucimibe is under development by Pierre Fabre and Eli Lilly entering phase II clinical trials in 2002. Unlike the statins which reduce LDL cholesterol in the blood, ACAT inhibitors may reduce both LDL levels and plaque that has built up on the vessel wall potentially reversing disease. If successful, ACAT inhibitors could represent a major advance over current statin therapies.

In a recent study de Medina et al demonstrated that the diphenylethane group of Sah 58-035, a prototypic ACAT inhibitor shared structural homology with the stilbene group of tamoxifen, an estrogen receptor modulator commonly used in the prevention and treatment of breast cancer (for an analysis of breast cancer therapeutics click here). Functionally Sah 58-035 and tamoxifen inhibited ACAT activity and interestingly the IC50 of the latter was similar to serum concentrations of tamoxifen measured following treatment with this drug. This study demonstrated that other estrogen receptor ligands were also able to inhibit ACAT and SAR studies were conducted revealing the structural requirements of tamoxifen-like compounds with ACAT inhibitory activity. Finally it was shown that tamoxifen was able to prevent the stimulation of ACAT activity in macrophages by acylated low-density lipoproteins and the resultant transformation of the macrophages into cells of characteristic foam cell appearance. These data offer a mechanism to explain the anti-atherogenic activity of tamoxifen in various animal models, as well clinical observations demonstrating that tamoxifen can reduce the risk of myocardial infarction. Furthermore, the SAR study may offer a platform for the rational design of novel ACAT inhibitors based on tamoxifen.

Finally there is significant co-morbidity between breast cancer and metabolic disease. For example obese post-menopausal women are over two-fold more likely to develop breast cancer. Obese individuals are also more likely than normal weight individuals to have hypercholesterolemia and atherosclerosis. It would therefore be interesting to compare the efficacy of tamoxifen, or other molecules that can both prevent breast cancer and inhibit ACAT on overall survival in obese and normal weight women being treated prophylactically for breast cancer.

Entry date Thursday, January 22, 2004

Adapted from De Medina et al, J Pharmacol Exp Ther. 2003 Nov 14 [Epub ahead of print]